Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof

ABSTRACT

The present application relates to new, substituted 2-acetamido-5-aryl-1,2,4-triazolones, to processes for preparing them, to their use alone or in combinations for the treatment and/or prevention of diseases and also to their use for the production of medicaments for the treatment and/or prevention of diseases, more particularly for the treatment and/or prevention of cardiovascular disorders.

The present application relates to new, substituted2-acetamido-5-aryl-1,2,4-triazolones, to processes for preparing them,to their use alone or in combinations for the treatment and/orprevention of diseases and also to their use for the production ofmedicaments for the treatment and/or prevention of diseases, moreparticularly for the treatment and/or prevention of cardiovasculardisorders.

The liquid content of the human body is subject to various physiologicalcontrol mechanisms the purpose whereof is to keep it constant (volumehomeostasis). In the process, both the volume filling of the vascularsystem and also the osmolarity of the plasma are continuously recordedby appropriate sensors (baroreceptors and osmoreceptors). Theinformation which these sensors supply to the relevant centres in thebrain regulate drinking behaviour and control fluid excretion via thekidneys by means of humoral and neural signals. The peptide hormonevasopressin is of central importance in this [Schrier R. W., Abraham, W.T., New Engl. J. Med. 341, 577-585 (1999)].

Vasopressin is produced in specialized endocrine neurones in the Nucleussupraopticus and N. paraventricularis in the wall of the third ventricle(hypothalamus) and transported from there along its neural processesinto the posterior lobes of the hypophysis (neurohypophysis). There thehormone is released into the bloodstream according to stimulus. A lossof volume, e.g. as a result of acute bleeding, heavy sweating, prolongedthirst or diarrhoea, is a stimulus for intensified outpouring of thehormone. Conversely, the secretion of vasopressin is inhibited by anincrease in the intravascular volume, e.g. as result of increased fluidintake.

Vasopressin exerts its action mainly via binding to three receptors,which are classified as V1a, V1b and V2 receptors and belong to thefamily of G protein-coupled receptors. V1a receptors are mainly locatedon the cells of the vascular smooth musculature. Their activation givesrise to vasoconstriction, as a result of which the peripheral resistanceand blood pressure rise. Apart from this, V1a receptors are alsodetectable in the liver. V1b receptors (also named V3 receptors) aredetectable in the central nervous system. Together withcorticotropin-releasing hormone (CRH), vasopressin regulates the basaland stress-induced secretion of adrenocorticotropic hormone (ACTH) viathe V1b receptor. V2 receptors are located in the distal tubularepithelium and the epithelium of the collecting tubules in the kidney.Their activation renders these epithelia permeable to water. Thisphenomenon is due to the incorporation of aquaporins (special waterchannels) in the luminal membrane of the epithelial cells.

The importance of vasopressin for the reabsorption of water from theurine in the kidney becomes clear from the clinical picture of diabetesinsipidus, which is caused by a deficiency of the hormone, e.g. owing tohypophysis damage. Patients who suffer from this clinical pictureexcrete up to 20 litres of urine per 24 hours if they are not givenreplacement hormone. This volume corresponds to about 10% of the primaryurine. Because of its great importance for the reabsorption of waterfrom the urine, vasopressin is also synonymously referred to asantidiuretic hormone (ADH). Logically, pharmacological inhibition of theaction of vasopressin/ADH on the V2 receptor results in increased urineexcretion. In contrast to the action of other diuretics (thiazides andloop diuretics), however, V2 receptor antagonists cause increased waterexcretion, without substantially increasing the excretion ofelectrolytes. This means that by means of V2 antagonist drugs, volumehomeostasis can be restored, without in the process affectingelectrolyte homeostasis. Hence drugs with V2 antagonist activity appearparticularly suitable for the treatment of all disease conditions whichare associated with an overloading of the body with water, without theelectrolytes being effectively increased in parallel. A significantelectrolyte abnormality is measurable in clinical chemistry ashyponatraemia (sodium concentration <135 mmol/L); it is the mostimportant electrolyte abnormality in hospital patients, with anincidence of ca. 5% or 250 000 cases per year in the USA alone. If theplasma sodium concentration falls below 115 mmol/L, comatose states anddeath are imminent.

Depending on the underlying cause, a distinction is made betweenhypovolaemic, euvolaemic and hypervolaemic hyponatraemia. The forms ofhypervolaemia with oedema formation are clinically significant. Typicalexamples of this are syndrome of inappropriate ADH/vasopressin secretion(SIAD) (e.g. after craniocerebral trauma or as paraneoplasia incarcinomas) and hypervolaemic hyponatraemia in liver cirrhosis, variousrenal diseases and cardiac insufficiency [De Luca L. et al., Am. J.Cardiol. 96 (suppl.), 19L-23L (2005)]. In particular, patients withcardiac insufficiency, in spite of their relative hyponatraemia andhypervolaemia, often display elevated vasopressin levels, which is seenas the consequence of generally disturbed neurohumoral regulation incardiac insufficiency [Francis G. S. et al., Circulation 82, 1724-1729(1990)].

The disturbed neurohormonal regulation essentially manifests itself inan elevation of the sympathetic tone and inappropriate activation of therenin-angiotensin-aldosterone system. While the inhibition of thesecomponents by beta receptor blockers on the one hand and by ACEinhibitors or angiotensin receptor blockers on the other is now aninherent part of the pharmacological treatment of cardiac insufficiency,the inappropriate elevation of vasopressin secretion in advanced cardiacinsufficiency is at present still not adequately treatable. Apart fromthe retention of water mediated by V2 receptors and the unfavourablehaemodynamic consequences associated therewith in terms of increasedbackload, the emptying of the left ventricle, the pressure in thepulmonary blood vessels and cardiac output are also adversely affectedby V1a-mediated vasoconstriction. Furthermore, on the basis ofexperimental data in animals, a direct hypertrophy-promoting action onthe heart muscle is also attributed to vasopressin. In contrast to therenal effect of volume expansion, which is mediated by activation of V2receptors, the direct action on the heart muscle is triggered byactivation of V1a receptors.

For these reasons, substances which inhibit the action of vasopressin onthe V2 and/or on the V1a receptor appear suitable for the treatment ofcardiac insufficiency. In particular, compounds with combined activityon both vasopressin receptors (V1a and V2) should both have desirablerenal and also haemodynamic effects and thus offer an especially idealprofile for the treatment of patients with cardiac insufficiency. Theprovision of such combined vasopressin antagonists also appears to makesense inasmuch as a volume diminution mediated solely via V2 receptorblockade can entail the stimulation of osmoreceptors and as a result afurther compensatory increase in vasopressin release. As a result, inthe absence of a component simultaneously blocking the V1a receptor, theharmful effects of the vasopressin, such as for example vasoconstrictionand heart muscle hypertrophy, could be further intensified [Saghi P. etal., Europ. Heart J. 26, 538-543 (2005)].

WO 99/54315 discloses substituted triazolones with neuroprotectiveactivity, and WO 2006/117657 describes triazolone derivatives asanti-inflammatory agents. Furthermore, EP 503 548-A1 and EP 587 134-A2claim cyclic urea derivatives and their use for the treatment ofthromboses. Substituted triazole thiones as ion channel modulators aredisclosed in WO 2005/097112. WO 2007/134862 describes substitutedimidazol-2-ones and 1,2,4-triazolones as vasopressin receptorantagonists for the treatment of cardiovascular disorders.

It is an object of the present invention to provide new compounds whichact as potent, selective dual V1a/V2 receptor antagonists and are suchas suitable for the treatment and/or prevention of diseases, moreparticularly for the treatment and/or prevention of cardiovasculardisorders.

The present invention provides compounds of the general formula (I)

in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen, (C₁-C₄) alkyl or trifluoromethyl,    -   R^(6B) is hydrogen or (C₁-C₄) alkyl,    -   R^(7A) is hydrogen, (C₁-C₄) alkyl or trifluoromethyl,    -   R^(7B) is hydrogen or (C₁-C₄) alkyl,-   Q is CH or N,-   R¹ is (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl or (C₃-C₇)    cycloalkyl,    -   where (C₁-C₆) alkyl, (C₂-C₆) alkenyl and (C₂-C₆) alkynyl may be        substituted by 1 to 3 substituents independently of one another        selected from the group consisting of deuterium, halogen, cyano,        oxo, hydroxyl, trifluoromethyl, (C₃-C₇) cycloalkyl, (C₁-C₆)        alkoxy, trifluoromethoxy and phenyl,        -   in which (C₃-C₇) cycloalkyl may be substituted by 1 or 2            substituents independently of one another selected from the            group consisting of (C₁-C₄) alkyl, oxo, hydroxyl, (C₁-C₄)            alkoxy and amino,        -   and        -   in which (C₁-C₆) alkoxy may be substituted by 1 or 2            substituents independently of one another selected from the            group consisting of amino, hydroxyl, (C₁-C₄) alkoxy,            hydroxycarbonyl and (C₁-C₄) alkoxycarbonyl,        -   and        -   in which phenyl may be substituted by 1 to 3 substituents            independently of one another selected from the group            consisting of halogen, cyano, nitro, (C₁-C₄) alkyl,            trifluoromethyl, hydroxyl, hydroxymethyl, (C₁-C₄) alkoxy,            trifluoromethoxy, (C₁-C₄) alkoxymethyl, hydroxycarbonyl,            (C₁-C₄) alkoxycarbonyl, aminocarbonyl, mono-(C₁-C₄)            alkylaminocarbonyl and di-(C₁-C₄) alkylaminocarbonyl,    -   and    -   where (C₃-C₇) cycloalkyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of fluorine, (C₁-C₄) alkyl, (C₁-C₄) alkoxy,        hydroxy, amino and oxo,-   R² is benzothienyl, phenyl, thienyl or furyl,    -   where benzothienyl, phenyl, thienyl and furyl may be substituted        by 1 to 3 substituents independently of one another selected        from the group consisting of halogen, cyano, nitro, (C₁-C₄)        alkyl, trifluoromethyl, hydroxyl, (C₁-C₄) alkoxy and        trifluoromethoxy,-   R³ is trifluoromethyl, hydroxyl, trifluoromethoxy, (C₁-C₄) alkoxy,    (C₃-C₇) cycloalkoxy, nitro, amino, —NR⁸—C(═O)—R⁹, —NR¹⁰—SO₂—R¹¹,    —SO₂—NR¹²R¹³, —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸,    —NR¹⁹—C(═O)—OR²⁰, —S(═O)_(n)R²¹, —O—SO₂—NR²⁴R²⁵, —NR²⁶—SO₂—NR²⁷R²⁸    or —NR³⁰R³¹,-   where    -   R⁸ is hydrogen or (C₁-C₄) alkyl,    -   R⁹ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R⁸ and R⁹ together with the atoms to which they are attached        form a 5- to 7-membered heterocycle,        -   where the 5- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, (C₁-C₄) alkyl and            trifluoromethyl,    -   R¹⁰ is hydrogen or (C₁-C₄) alkyl,    -   R¹¹ is (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁰ and R¹¹ together with the atoms to which they are attached        form a 5- to 7-membered heterocycle,        -   where the 5- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, (C₁-C₄) alkyl and            trifluoromethyl,    -   R¹² is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R¹³ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹² and R¹³ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl,            (C₁-C₄) alkyl and trifluoromethyl,    -   R¹⁴ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R¹⁵ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁴ and R¹⁵ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl,            (C₁-C₄) alkyl and trifluoromethyl,    -   R¹⁶ is hydrogen or (C₁-C₄) alkyl,    -   R¹⁷ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R¹⁸ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 5- to 7-membered heterocycle,        -   where the 5- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, trifluoromethyl and            (C₁-C₄) alkyl,    -   or    -   R¹⁷ and R¹⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl,            (C₁-C₄) alkyl and trifluoromethyl,    -   R¹⁹ is hydrogen or (C₁-C₄) alkyl,    -   R²⁰ is (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 5- to 7-membered heterocycle,        -   where the 5- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, (C₁-C₄) alkyl and            trifluoromethyl,    -   n is a number 0, 1 or 2,    -   R²¹ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R²⁴ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R²⁵ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R²⁴ and R²⁵ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl,            (C₁-C₄) alkyl and trifluoromethyl,    -   R²⁶ is hydrogen or (C₁-C₄) alkyl,    -   R²⁷ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R²⁸ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R²⁶ and R²⁷ together with the nitrogen atoms to which they are        attached form a 5- to 7-membered heterocycle,        -   where the 5- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, trifluoromethyl and            (C₁-C₄) alkyl,    -   or    -   R²⁷ and R²⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl and            (C₁-C₄) alkyl,    -   R³⁰ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R³¹ is (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R³⁰ and R³¹ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl,            (C₁-C₄) alkyl and trifluoromethyl,-   R⁴ is phenyl, naphthyl or 5- to 10-membered heteroaryl,    -   where phenyl, naphthyl and 5- to 10-membered heteroaryl may be        substituted by 1 to 3 substituents independently of one another        selected from the group consisting of halogen, cyano, nitro,        (C₁-C₄) alkyl, difluoromethyl, trifluoromethyl, hydroxyl,        (C₁-C₄) alkoxy, difluoromethoxy and trifluoromethoxy,-   R⁵ is hydrogen, deuterium, trifluoromethyl or (C₁-C₄) alkyl,-   R²⁹ is hydrogen or (C₁-C₄) alkyl,    and also their salts, solvates, and solvates of the salts.

Compounds according to the invention are the compounds of the formula(I) and their salts, solvates, and solvates of the salts; the compoundsof the below-specified formulae embraced by formula (I), and theirsalts, solvates, and solvates of the salts; and also the compoundsspecified below as working examples and embraced by formula (I), andtheir salts, solvates, and solvates of the salts; in so far as thebelow-specified compounds embraced by formula (I) are not already salts,solvates, and solvates of the salts.

Depending on their structure, the compounds according to the inventionmay exist in stereoisomeric forms (enantiomers, diastereomers). Thepresent invention therefore embraces the enantiomers or diastereomersand their respective mixtures. From such mixtures of enantiomers and/ordiastereomers it is possible to isolate the stereoisomerically uniformconstituents in a known way.

Where the compounds according to the invention are able to occur intautomeric forms, the present invention embraces all of the tautomericforms.

Salts preferred in the context of the present invention arephysiologically unobjectionable salts of the compounds of the invention.Also embraced are salts which, while not themselves suitable forpharmaceutical applications, may nevertheless be used, for example, forthe isolation or purification of the compounds of the invention.

Physiologically unobjectionable salts of the compounds of the inventionembrace acid addition salts of mineral acids, carboxylic acids andsulphonic acids, examples being salts of hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid,ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid,propionic acid, lactic acid, tartaric acid, maleic acid, citric acid,fumaric acid, maleic acid and benzoic acid.

Physiologically unobjectionable salts of the compounds of the inventionalso embrace salts with customary bases, such as—by way of example andpreferably—alkali metal salts (e.g. sodium and potassium salts),alkaline earth metal salts (e.g. calcium and magnesium salts) andammonium salts, derived from ammonia or from organic amines having 1 to16 C atoms, such as—by way of example and preferably-ethylamine,diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, trisethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates in the context of the invention are those forms of thecompounds of the invention that form a complex in solid or liquid stateby coordination with solvent molecules. Hydrates are one specific formof solvates, where the coordination is with water. Preferred solvates inthe context of the present invention are hydrates.

Furthermore, the present invention also embraces prodrugs of thecompounds of the invention. The term “prodrugs” embraces compounds whichmay themselves be biologically active or inactive but which during theirresidence time in the body are converted (metabolically or byhydrolysis, for example) into compounds of the invention.

In the context of the present invention, the substituents, unlessotherwise specified, have the following definitions:

Alkyl in the context of the invention is a linear or branched alkylradical having 1 to 6 or 1 to 4 carbon atoms. By way of example and forpreference it includes the following: methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl,isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,3,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.

Cycloalkyl in the context of the invention is a monocyclic saturatedalkyl radical having 3 to 7 or 3 to 6 carbon atoms. By way of exampleand for preference it includes the following: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

Alkenyl in the context of the invention is a linear or a branchedalkenyl radical having 2 to 6 carbon atoms and one or two double bonds.Preference is given to a straight-chain or branched alkenyl radicalhaving 2 to 4 carbon atoms and one double bond. By way of example andfor preference it includes the following: vinyl, allyl, isopropenyl andn-but-2-en-1-yl.

Alkynyl in the context of the invention is a linear or branched alkynylradical having 2 to 6 carbon atoms and one triple bond. By way ofexample and for preference it includes the following: ethynyl,n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl.

Alkoxy in the context of the invention is a linear or branched alkoxyradical having 1 to 6 or 1 to 4 carbon atoms. By way of example and forpreference it includes the following: methoxy, ethoxy, n-propoxy,isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.

Cycloalkoxy in the context of the invention is a monocyclic saturatedcycloalkyl radical having 3 to 7 carbon atoms which is attached via anoxygen atom. By way of example and for preference it includes thefollowing: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxyand cycloheptyloxy.

Alkoxycarbonyl in the context of the invention is a linear or branchedalkoxy radical having 1 to 6 carbon atoms and a carbonyl group attachedto the oxygen. By way of example and for preference it includes thefollowing: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl and tert-butoxycarbonyl.

Mono-alkylaminocarbonyl in the context of the invention is an aminogroup which is linked via a carbonyl group and which has a linear orbranched alkyl substituent having 1 to 4 carbon atoms. By way of exampleand for preference it includes the following: methylaminocarbonyl,ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl,n-butylaminocarbonyl and tert-butylaminocarbonyl.

Di-alkylaminocarbonyl in the context of the invention is an amino groupwhich is linked via a carbonyl group and which has two identical ordifferent linear or branched alkyl substituents each having 1 to 4carbon atoms. By way of example and for preference it includes thefollowing: N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl,N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl,N-n-butyl-N-methylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.

Heterocycle in the context of the invention is a saturated or partiallyunsaturated heterocycle having a total of 4 to 7 ring atoms, whichcomprises one to three ring heteroatoms from the series N, O and/or S,and is linked via a ring carbon atom or possibly a ring nitrogen atom.By way of example it includes the following: azetidinyl, pyrrolidinyl,piperidinyl, azepanyl, pyrazolidinyl, imidazolidinyl, piperazinyl,tetrahydropyrimidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl,diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazinanyl,oxazepanyl,

2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxoazepan-1-yl,2-oxoimidazolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,2-oxotetrahydropyrimidin-1(2H)-yl, 2-oxo-1,3-oxazinan-3-yl,2-oxo-1,3-diazepan-1-yl, 2-oxo-1,3-oxazepan-3-yl,2,3-dihydro-1H-pyrrol-1-yl, 2-oxo-2,3-dihydro-1H-pyrrol-1-yl,2-oxo-2,5-dihydro-1H-pyrrol-1-yl, 2-oxo-1,3-oxazolidinyl-3-yl,2-oxo-1,3-oxazol-3(2H)-yl, 2-oxoimidazolidin-1-yl,2-oxo-2,3-dihydro-1H-imidazol-1-yl, 1,1-dioxido-1,2-thiazolidin-2-yl,1,1-dioxido-1,2-thiazinan-2-yl, 1,1-dioxido-1,2-thiazepan-2-yl,1,1-dioxido-1,2,5-thiadiazolidin-2-yl,1,1-dioxido-1,2,6-thiadiazinan-2-yl and1,1-dioxido-1,2,7-thiadiazepan-2-yl. Preference is given to azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, diazepanyl,oxazepanyl, 2-oxoimidazolidin-1-yl, 2-oxo-2,3-dihydro-1H-pyrrol-1-yl,2-oxo-2,5-dihydro-1H-pyrrol-1-yl, 2-oxo-1,3-oxazolidin-3-yl,1,1-dioxido-1,2,5-thiadiazolidin-2-yl,2-oxotetrahydropyrimidin-1(2H)-yl, 2-oxo-1,3-oxazinan-3-yl,2-oxo-1,3-diazepan-1-yl and 2-oxo-1,3-oxazepan-3-yl.

Heteroaryl in the context of the invention is a monocyclic or possiblybicyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 10ring atoms, which comprises up to three identical or different ringheteroatoms from the series N, O and/or S, and is linked via a ringcarbon atom or possibly via a ring nitrogen atom. By way of example itincludes the following: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl,isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, phthalazinyl,pyrazolo[3,4-b]pyridinyl. Preference is given to monocyclic 5- or6-membered heteroaryl radicals having up to three ring heteroatoms fromthe series N, O and/or S, such as, for example, furyl, thienyl,thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl,triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl.

Halogen the context of the invention includes fluorine, chlorine,bromine and iodine. Preference is given to chlorine or fluorine.

An oxo group in the context of the invention is an oxygen atom attachedvia a double bond to a carbon atom.

If radicals in the compounds of the invention are substituted, theradicals, unless otherwise specified, may be substituted one or moretimes. In the context of the present invention it is the case that, forall radicals which occur more than once, their definitions areindependent of one another. Substitution by one, two or three identicalor different substituents is preferred. Very particular preference isgiven to substitution by one substituent.

Preference in the context of the present invention is given to compoundsof the general formula (I-B)

in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen, (C₁-C₄) alkyl or trifluoromethyl,    -   R^(6B) is hydrogen or (C₁-C₄) alkyl,    -   R^(7A) is hydrogen, (C₁-C₄) alkyl or trifluoromethyl,    -   R^(7B) is hydrogen or (C₁-C₄) alkyl,-   R¹ is (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl or (C₃-C₇)    cycloalkyl, where (C₁-C₆) alkyl, (C₂-C₆) alkenyl and (C₂-C₆) alkynyl    may be substituted by 1 to 3 substituents independently of one    another selected from the group consisting of halogen, cyano, oxo,    hydroxyl, trifluoromethyl, (C₃-C₇) cycloalkyl, (C₁-C₆) alkoxy,    trifluoromethoxy and phenyl,    -   -   in which (C₃-C₇) cycloalkyl may be substituted by 1 or 2            substituents independently of one another selected from the            group consisting of (C₁-C₄) alkyl, oxo, hydroxyl, (C₁-C₄)            alkoxy and amino,        -   and        -   in which (C₁-C₆) alkoxy may be substituted by 1 or 2            substituents independently of one another selected from the            group consisting of amino, hydroxyl, (C₁-C₄) alkoxy,            hydroxycarbonyl and (C₁-C₄) alkoxycarbonyl,        -   and        -   in which phenyl may be substituted by 1 to 3 substituents            independently of one another selected from the group            consisting of halogen, cyano, nitro, (C₁-C₄) alkyl,            trifluoromethyl, hydroxyl, hydroxymethyl, (C₁-C₄)alkoxy,            trifluoromethoxy, (C₁-C₄) alkoxymethyl, hydroxycarbonyl,            (C₁-C₄) alkoxycarbonyl, aminocarbonyl, mono-(C₁-C₄)            alkylaminocarbonyl and di-(C₁-C₄) alkylaminocarbonyl,

    -   and

    -   where (C₃-C₇) cycloalkyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of fluorine, (C₁-C₄) alkyl, (C₁-C₄) alkoxy,        hydroxy, amino and oxo,-   R² is phenyl, thienyl or furyl,    -   where phenyl, thienyl and furyl may be substituted by 1 to 3        substituents independently of one another selected from the        group consisting of halogen, cyano, nitro, (C₁-C₄) alkyl,        trifluoromethyl, hydroxyl, (C₁-C₄) alkoxy and trifluoromethoxy,-   R³ is trifluoromethyl, hydroxyl, nitro, amino, —NR⁸—C(═O)—R⁹,    —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³, —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸,    —NR¹⁹—C(═O)—OR²⁰ or —S(═O)_(n)R²¹,-   where    -   R⁸ is hydrogen or (C₁-C₄) alkyl,    -   R⁹ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R¹⁰ is hydrogen or (C₁-C₄) alkyl,    -   R¹¹ is (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R¹² is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R¹³ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹² and R¹³ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl and            (C₁-C₄) alkyl,    -   R¹⁴ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R¹⁵ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁴ and R¹⁵ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl and            (C₁-C₄) alkyl,    -   R¹⁶ is hydrogen or (C₁-C₄) alkyl,    -   R¹⁷ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   R¹⁸ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 5- to 7-membered heterocycle,        -   where the 5- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine and (C₁-C₄) alkyl,    -   or    -   R¹⁷ and R¹⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,        -   where the 4- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine, oxo, hydroxyl and            (C₁-C₄) alkyl,    -   R¹⁹ is hydrogen or (C₁-C₄) alkyl,    -   R²⁰ is (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 5- to 7-membered heterocycle,        -   where the 5- to 7-membered heterocycle may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of fluorine and (C₁-C₄) alkyl,    -   n is a number 0, 1 or 2,    -   R²¹ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,-   R⁴ is phenyl, naphthyl or 5- to 10-membered heteroaryl,    -   where phenyl, naphthyl and 5- to 10-membered heteroaryl may be        substituted by 1 to 3 substituents independently of one another        selected from the group consisting of halogen, cyano, nitro,        (C₁-C₄) alkyl, difluoromethyl, trifluoromethyl, hydroxyl,        (C₁-C₄) alkoxy, difluoromethoxy and trifluoromethoxy,-   R⁵ is hydrogen, trifluoromethyl or (C₁-C₄) alkyl,    and also their salts, solvates, and solvates of the salts.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen, methyl or trifluoromethyl,    -   R^(6B) is hydrogen or methyl,    -   R^(7A) is hydrogen, methyl or trifluoromethyl,    -   R^(7B) is hydrogen or methyl,

Q is CH or N,

-   -   R¹ is (C₁-C₆) alkyl, (C₂-C₆) alkenyl or (C₃-C₆) cycloalkyl,        where (C₁-C₆) alkyl and (C₂-C₆) alkenyl may be substituted by 1        to 3 substituents independently of one another selected from the        group consisting of fluorine, chlorine, cyano, oxo, hydroxyl,        trifluoromethyl, (C₃-C₆) cycloalkyl, (C₁-C₄) alkoxy,        trifluoromethoxy and phenyl,        -   in which (C₃-C₆) cycloalkyl may be substituted by 1 or 2            substituents independently of one another selected from the            group consisting of methyl, ethyl, oxo, hydroxyl, methoxy,            ethoxy and amino,        -   and        -   in which phenyl may be substituted by a substituent selected            from the group consisting of fluorine, chlorine, cyano,            methyl, ethyl, trifluoromethyl, methoxy, ethoxy,            trifluoromethoxy, methoxymethyl, ethoxymethyl,            hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and            aminocarbonyl,    -   and    -   where (C₃-C₆) cycloalkyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of fluorine, methyl, ethyl, methoxy, ethoxy,        hydroxyl, amino and oxo,

-   R² is benzothien-2-yl, phenyl or thienyl,    -   where benzothien-2-yl, phenyl and thienyl may be substituted by        1 or 2 substituents independently of one another selected from        the group consisting of fluorine, chlorine, bromine, methyl,        ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy and        trifluoromethoxy,

-   R³ is trifluoromethyl, hydroxyl, amino, —NR⁸—C(═O)—R⁹,    —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³, —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸,    —NR¹⁹—C(═O)—OR²⁰, —S(═O)_(n)R²¹, —O—SO₂—NR²⁴R²⁵ or    —NR²⁶—SO₂—NR²⁷R²⁸—,    -   where    -   R⁸ is hydrogen or methyl,    -   R⁹ is (C₁-C₄) alkyl,    -   or    -   R⁸ and R⁹ together with the atoms to which they are attached        form a 5- to 7-membered heterocycle,    -   R¹⁰ is hydrogen or methyl,    -   R¹¹ is (C₁-C₄) alkyl,    -   or    -   R¹⁰ and R¹¹ together with the atoms to which they are attached        form a 5- to 7-membered heterocycle,    -   R¹² is (C₁-C₄) alkyl,    -   R¹³ is (C₁-C₄) alkyl,    -   R¹⁴ is hydrogen or (C₁-C₄) alkyl,    -   R¹⁵ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁴ and R¹⁵ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle,    -   R¹⁶ is hydrogen or (C₁-C₄) alkyl,    -   R¹⁷ is hydrogen or (C₁-C₄) alkyl,    -   R¹⁸ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 5- to 7-membered heterocycle,    -   R¹⁹ is hydrogen or methyl,    -   R²⁰ is (C₁-C₄) alkyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 5- to 7-membered heterocycle,    -   n is a number 0, 1 or 2,    -   R²¹ is (C₁-C₄) alkyl,    -   R²⁴ is hydrogen or methyl,    -   R²⁵ is hydrogen or methyl,    -   R²⁶ is hydrogen or methyl,    -   R²⁷ is hydrogen or (C₁-C₄) alkyl,    -   R²⁸ is hydrogen or (C₁-C₄) alkyl,    -   or    -   R²⁶ and R²⁷ together with the nitrogen atoms to which they are        attached form a 5- to 7-membered heterocycle,

-   R⁴ is phenyl,    -   where phenyl may be substituted by 1 to 3 substituents        independently of one another selected from the group consisting        of fluorine, chlorine, cyano, methyl, ethyl, difluoromethyl,        trifluoromethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy and        trifluoromethoxy,

-   R⁵ is hydrogen, deuterium, trifluoromethyl, methyl or ethyl,

-   R²⁹ is hydrogen or methyl,    and also their salts, solvates, and solvates of the salts.

Preference is given in the context of the present invention to compoundsof the formula (I-B) in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen, methyl or trifluoromethyl,    -   R^(6B) is hydrogen or methyl,    -   R^(7A) is hydrogen, methyl or trifluoromethyl,    -   R^(7B) is hydrogen or methyl,    -   R¹ is (C₁-C₆) alkyl, (C₂-C₆) alkenyl or (C₃-C₆) cycloalkyl,        -   where (C₁-C₆) alkyl and (C₂-C₆) alkenyl may be substituted            by 1 to 3 substituents independently of one another selected            from the group consisting of fluorine, chlorine, cyano, oxo,            hydroxyl, trifluoromethyl, (C₃-C₆) cycloalkyl, (C₁-C₄)            alkoxy, trifluoromethoxy and phenyl,            -   in which (C₃-C₆) cycloalkyl may be substituted by 1 or 2                substituents independently of one another selected from                the group consisting of methyl, ethyl, oxo, hydroxyl,                methoxy, ethoxy and amino,            -   and            -   in which phenyl may be substituted by a substituent                selected from the group consisting of fluorine,                chlorine, cyano, methyl, ethyl, trifluoromethyl,                methoxy, ethoxy, trifluoromethoxy, methoxymethyl,                ethoxymethyl, hydroxycarbonyl, methoxycarbonyl,                ethoxycarbonyl and aminocarbonyl,    -   and    -   where (C₃-C₆) cycloalkyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of fluorine, methyl, ethyl, methoxy, ethoxy,        hydroxyl, amino and oxo,-   R² is phenyl or thienyl,    -   where phenyl and thienyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of fluorine, chlorine, methyl, ethyl,        trifluoromethyl, hydroxyl, methoxy, ethoxy and trifluoromethoxy,-   R³ is trifluoromethyl, hydroxyl, amino, —NR⁸—C(═O)—R⁹,    —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³, —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸    or —NR¹⁹—C(═O)—OR²⁰,    -   where    -   R⁸ is hydrogen or methyl,    -   R⁹ is (C₁-C₄) alkyl,    -   R¹⁰ is hydrogen or methyl,    -   R¹¹ is (C₁-C₄) alkyl,    -   R¹² is (C₁-C₄) alkyl,    -   R¹³ is (C₁-C₄) alkyl,    -   R¹⁴ is hydrogen or (C₁-C₄) alkyl,    -   R¹⁵ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁴ and R¹⁵ together with the nitrogen atom to which they are        attached form a 4- to 6-membered heterocycle,    -   R¹⁶ is hydrogen or (C₁-C₄) alkyl,    -   R¹⁷ is hydrogen or (C₁-C₄) alkyl,    -   R¹⁸ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,    -   or    -   R¹⁷ and R¹⁸ together with the nitrogen atom to which they are        attached form a 4- to 6-membered heterocycle,    -   R¹⁹ is hydrogen or methyl,    -   R²⁰ is (C₁-C₄) alkyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 5- or 6-membered heterocycle,-   R⁴ is phenyl,    -   where phenyl may be substituted by 1 to 3 substituents        independently of one another selected from the group consisting        of fluorine, chlorine, cyano, methyl, ethyl, difluoromethyl,        trifluoromethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy and        trifluoromethoxy,-   R⁵ is hydrogen, trifluoromethyl, methyl or ethyl,    and also their salts, solvates, and solvates of the salts.

Particular preference is given in the context of the present inventionto compounds of the formula (I) in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen or trifluoromethyl,    -   R^(6B) is hydrogen,    -   R^(7A) is hydrogen,    -   R^(7B) is hydrogen,-   Q is N,-   R¹ is (C₂-C₄) alkyl, (C₂-C₄) alkenyl or cyclopropyl,    -   where (C₂-C₄) alkyl and (C₂-C₄) alkenyl may be substituted by 1        or 2 substituents independently of one another selected from the        group consisting of fluorine, oxo, hydroxyl and trifluoromethyl,-   R² is phenyl,    -   where phenyl may be substituted by a substituent selected from        the group consisting of fluorine or chlorine,-   R³ is hydroxyl, amino, —NR⁸—C(═O)—R⁹, —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³,    —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸, —NR¹⁹—C(═O)—OR²⁰,    —S(═O)_(n)R²¹ or —NR²⁶—SO₂—NR²⁷R²⁸—,    -   where    -   R⁸ is hydrogen,    -   R⁹ is methyl,    -   R¹⁰ is hydrogen,    -   R¹¹ is methyl or ethyl,    -   R¹² is methyl,    -   R¹³ is methyl,    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,    -   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl,    -   or    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 2-oxoimidazolidin-1-yl or a        2-oxotetrahydropyrimidin-1(2H)-yl ring,    -   R¹⁹ is hydrogen,    -   R²⁰ is methyl or ethyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl        ring,    -   n is a number 0 or 2,    -   R²¹ is methyl,    -   R²⁶ is hydrogen,    -   R²⁷ is hydrogen,    -   R²⁸ is hydrogen,    -   R⁴ is a group of the formula

-   -   where    -   # is the attachment site to —C(R⁵)(AR³)N—,    -   R²² is hydrogen, cyano, methyl, trifluoromethoxy, fluorine,        chlorine, trifluoromethyl and methoxy,    -   R²³ is hydrogen, cyano, methyl, trifluoromethoxy, fluorine,        chlorine, trifluoromethyl and methoxy,    -   where at least one of the radicals R²² and R²³ is other than        hydrogen,

-   R⁵ is hydrogen or methyl,

-   R²⁹ is hydrogen,    and also their salts, solvates, and solvates of the salts.

Particular preference is additionally given in the context of thepresent invention to compounds of the formula (I) in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen or trifluoromethyl,    -   R^(6B) is hydrogen,    -   R^(7A) is hydrogen,    -   R^(7B) is hydrogen,-   Q is N,-   R¹ is (C₂-C₄) alkyl, (C₂-C₄) alkenyl or cyclopropyl, where (C₂-C₄)    alkyl and (C₂-C₄) alkenyl may be substituted by 1 or 2 substituents    independently of one another selected from the group consisting of    fluorine, oxo, hydroxyl and trifluoromethyl,-   R² is phenyl,    -   where phenyl may be substituted by a substituent selected from        the group consisting of fluorine or chlorine,-   R³ is trifluoromethyl, hydroxyl, amino, —NR⁸—C(═O)—R⁹,    —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³, —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸,    —NR¹⁹—C(═O)—OR²⁰, —S(═O)_(n)R²¹ or —NR²⁶—SO₂—NR²⁷R²⁸—,    -   where    -   R⁸ is hydrogen,    -   R⁹ is methyl,    -   R¹⁰ is hydrogen,    -   R¹¹ is methyl or ethyl,    -   R¹² is methyl,    -   R¹³ is methyl,    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,    -   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl,    -   or    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 2-oxoimidazolidin-1-yl or a        2-oxotetrahydropyrimidin-1(2H)-yl ring,    -   R¹⁹ is hydrogen,    -   R²⁰ is methyl or ethyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl        ring,    -   n is a number 0 or 2,    -   R²¹ is methyl,    -   R²⁶ is hydrogen,    -   R²⁷ is hydrogen,    -   R²⁸ is hydrogen,-   R⁴ is a group of the formula

-   -   where    -   # is the attachment site to —C(R⁵)(AR³)N—,    -   R²² is hydrogen, fluorine, chlorine, trifluoromethyl and        methoxy,    -   R²³ is hydrogen, fluorine, chlorine, trifluoromethyl and        methoxy,    -   where at least one of the radicals R²² and R²³ is other than        hydrogen,

-   R⁵ is hydrogen or methyl,

-   R²⁹ is hydrogen,    and also their salts, solvates, and solvates of the salts.

More particular preference is given in the context of the presentinvention to compounds of the formula (I) in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen or trifluoromethyl,    -   R^(6B) is hydrogen,    -   R^(7A) is hydrogen,    -   R^(7B) is hydrogen,-   Q is N,-   R¹ is 3,3,3-trifluoroprop-1-en-1-yl, 3,3,3-trifluoropropyl or    1,1,1-trifluoropropan-2-ol-3-yl,-   R² is phenyl,    -   where phenyl may be substituted by a substituent selected from        the group consisting of fluorine or chlorine,-   R³ is hydroxyl, amino, —NR⁸—C(═O)—R⁹, —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³,    —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸, —NR¹⁹—C(═O)—OR²⁰,    —S(═O)_(n)R²¹ or —NR²⁶—SO₂—NR²⁷R²⁸—,    -   where    -   R⁸ is hydrogen,    -   R⁹ is methyl,    -   R¹⁰ is hydrogen,    -   R¹¹ is methyl or ethyl,    -   R¹² is methyl,    -   R¹³ is methyl,    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,    -   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl,    -   or    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 2-oxoimidazolidin-1-yl or a        2-oxotetrahydropyrimidin-1(2H)-yl ring,    -   R¹⁹ is hydrogen,    -   R²⁰ is methyl or ethyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl        ring,    -   n is a number 0 or 2,    -   R²¹ is methyl,    -   R²⁶ is hydrogen,    -   R²⁷ is hydrogen,    -   R²⁸ is hydrogen,-   R⁴ is a group of the formula

-   -   where    -   # is the attachment site to —C(R⁵)(AR³)N—,    -   R²² is hydrogen, fluorine, chlorine and trifluoromethyl,    -   R²³ is hydrogen, fluorine, chlorine and trifluoromethyl,    -   where at least one of the radicals R²² and R²³ is other than        hydrogen,

-   R⁵ is hydrogen or methyl,

-   R²⁹ is hydrogen,    and also their salts, solvates, and solvates of the salts.

Particular preference is given in the context of the present inventionto compounds of the formula (I-B) in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen or trifluoromethyl,    -   R^(6B) is hydrogen,    -   R^(7A) is hydrogen,    -   R^(7B) is hydrogen,-   R¹ is (C₂-C₄) alkyl, (C₂-C₄) alkenyl or cyclopropyl,    -   where (C₂-C₄) alkyl and (C₂-C₄) alkenyl are substituted by 1 or        2 substituents independently of one another selected from the        group consisting of fluorine, hydroxyl, oxo and trifluoromethyl,-   R² is phenyl,    -   where phenyl is substituted by a substituent selected from the        group consisting of fluorine and chlorine,-   R³ is trifluoromethyl, hydroxyl, amino, —NR⁸—C(═O)—R⁹,    —NR¹³—SO₂—R¹¹, —O—C(═O)—NR¹⁴R¹⁵ or —NR¹⁶—C(═O)—NR¹⁷R¹⁸,    -   where    -   R⁸ is hydrogen,    -   R⁹ is methyl,    -   R¹⁰ is hydrogen,    -   R¹¹ is methyl or ethyl,    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,    -   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl,-   R⁴ is a group of the formula

-   -   where    -   # is the attachment site to —C(R⁵)(AR³)N—,    -   R²² is hydrogen, cyano, methyl, trifluoromethoxy, fluorine,        chlorine, trifluoromethyl and methoxy,    -   R²³ is hydrogen, cyano, methyl, trifluoromethoxy, fluorine,        chlorine, trifluoromethyl and methoxy,    -   where at least one of the radicals R²² and R²³ is other than        hydrogen,

-   R⁵ is hydrogen or methyl,    and also their salts, solvates, and solvates of the salts.

Particular preference is additionally given in the context of thepresent invention to compounds of the formula (I-B) in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen or trifluoromethyl,    -   R^(6B) is hydrogen,    -   R^(7A) is hydrogen,    -   R^(7B) is hydrogen,-   R¹ is (C₂-C₄) alkyl, (C₂-C₄) alkenyl or cyclopropyl,    -   where (C₂-C₄) alkyl and (C₂-C₄) alkenyl are substituted by 1 or        2 substituents independently of one another selected from the        group consisting of fluorine, hydroxyl, oxo and trifluoromethyl,-   R² is phenyl,    -   where phenyl is substituted by a substituent selected from the        group consisting of fluorine and chlorine,-   R³ is trifluoromethyl, hydroxyl, amino, —NR⁸—C(═O)—R⁹,    —NR¹⁰—SO₂—R¹¹, —O—C(═O)—NR¹⁴R¹⁵ or —NR¹⁶—C(═O)—NR¹⁷R¹⁸,    -   where    -   R⁸ is hydrogen,    -   R⁹ is methyl,    -   R¹⁰ is hydrogen,    -   R¹¹ is methyl or ethyl,    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,    -   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl,-   R⁴ is a group of the formula

-   -   where    -   # is the attachment site to —C(R⁵)(AR³)N—,    -   R²² is hydrogen, fluorine, chlorine, trifluoromethyl and        methoxy,    -   R²³ is hydrogen, fluorine, chlorine, trifluoromethyl and        methoxy,    -   where at least one of the radicals R²² and R²³ is other than        hydrogen,

-   R⁵ is hydrogen or methyl,    and also their salts, solvates, and solvates of the salts.

More particular preference is given in the context of the presentinvention to compounds of the formula (I-B) in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen or trifluoromethyl,    -   R^(6B) is hydrogen,    -   R^(7A) is hydrogen,    -   R^(7B) is hydrogen,    -   R¹ is 3,3,3-trifluoroprop-1-en-1-yl, 3,3,3-trifluoropropyl or        1,1,1-trifluoropropan-2-ol-3-yl,-   R² is phenyl,    -   where phenyl is substituted by a substituent selected from the        group consisting of fluorine and chlorine,-   R³ is hydroxyl, amino, —NR⁸—C(═O)—R⁹, —NR¹⁰—SO₂—R¹¹,    —O—C(═O)—NR¹⁴R¹⁵ or —NR¹⁶—C(═O)—NR¹⁷R¹⁸,    -   where    -   R⁸ is hydrogen,    -   R⁹ is methyl,    -   R¹⁰ is hydrogen,    -   R¹¹ is methyl or ethyl,    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,    -   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl,-   R⁴ is a group of the formula

-   -   where    -   # is the attachment site to —C(R⁵)(AR³)N—,    -   R²² is hydrogen, fluorine, chlorine or trifluoromethyl,    -   R²³ is hydrogen, fluorine, chlorine or trifluoromethyl,    -   where at least one of the radicals R²² and R²³ is other than        hydrogen,

-   R⁵ is hydrogen or methyl,    and also their salts, solvates, and solvates of the salts.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R² is p-chlorophenyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which

-   R² is phenyl or thienyl,    -   where phenyl and thienyl may be substituted by a substituent        selected from the group consisting of fluorine, chlorine,        methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy and        trifluoromethoxy.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R¹ is3,3,3-trifluoroprop-1-en-1-yl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R¹ is 3,3,3-trifluoropropyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R¹ is1,1,1-trifluoropropan-2-ol-3-yl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which

-   R¹ is (C₂-C₄) alkyl or (C₂-C₄) alkenyl,    -   where (C₂-C₄) alkyl and (C₂-C₄) alkenyl are substituted by 1 or        2 substituents independently of one another selected from the        group consisting of fluorine, hydroxyl, oxo and trifluoromethyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R¹ is cyclopropyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which

-   R³ is —O—C(═O)—NR¹⁴R¹⁵ or —NR¹⁶—C(═O)—NR¹⁷R¹⁸,    -   where    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,    -   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which

-   R³ is —NR¹⁰—SO₂—R¹¹,    -   where    -   R¹⁰ is hydrogen and    -   R¹¹ is methyl or ethyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which

-   R³ is hydroxyl or amino.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which

-   R³ is —NR¹⁶—C(═O)—NR¹⁷R¹⁸ or —NR¹⁹—C(═O)—OR²⁰,    -   where    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 2-oxoimidazolidin-1-yl or a        2-oxotetrahydropyrimidin-1(2H)-yl ring,    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl        ring.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which

-   R³ is —NR¹⁶—C(═O)—NR¹⁷R¹⁸ or —NR¹⁹—C(═O)—OR²⁰,    -   where    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 2-oxo-imidazolidin-1-yl ring,    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 2-oxo-1,3-oxazolidin-3-yl ring.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which A is —CH₂—CH₂—.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which A is —CH₂—.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which Q is N.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which Q is CH.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R⁵ is hydrogen, trifluoromethyl,methyl or ethyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R⁵ is hydrogen.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R⁵ is methyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R⁵ is trifluoromethyl, methyl orethyl.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R²⁹ is hydrogen.

Preference is given in the context of the present invention as well tocompounds of the formula (I) in which R²⁹ is methyl.

The radical definitions given individually in the respectivecombinations and preferred combinations of radicals are also replacedarbitrarily, independently of the particular radical combinationsspecified, by radical definitions from other combinations.

Very particular preference is given to combinations from two or more ofthe above-mentioned ranges of preference.

The invention further provides a process for preparing the compounds ofthe formula (I) according to the invention, characterized in that

[A] a compound of the formula (II)

-   -   in which Q, R¹ and R² are each as defined above    -   is coupled in an inert solvent, with activation of the        carboxylic acid function, to a compound of the formula (III)

-   -   in which A, R³, R⁴, R⁵ and R²⁹ are each as defined above,        or        [B] a compound of the formula (IV)

-   -   in which Q, R¹ and R² are each as defined above    -   is reacted in an inert solvent, in the presence of a base, with        a compound of the formula (V)

-   -   in which A, R³, R⁴, R⁵ and R²⁹ are each as defined above    -   and    -   X′ is a leaving group, such as halogen, mesylate or tosylate,        for example,        and the resulting compounds of the formula (I) are converted        optionally with the corresponding (i) solvents and/or (ii) bases        or acids into their solvates, salts and/or solvates of the        salts.

Inert solvents for the process step (II)+(III)→(I) are for exampleethers such as diethyl ether, dioxan, tetrahydrofuran, glycol dimethylether or diethylene glycol dimethyl ether, hydrocarbons such as benzene,toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenatedhydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, 1,2-dichloroethane, trichloroethylene orchlorobenzene, or other solvents such as acetone, ethyl acetate,acetonitrile, pyridine, dimethyl sulphoxide, N,N-dimethylformamide,N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Likewiseit is possible to use mixtures of the said solvents. Dichloro-methane,tetrahydrofuran, dimethylformamide or mixtures of these solvents arepreferred.

Suitable condensation agents for the amidation in the process step(II)+(III)→(I) include, for example, carbodiimides such asN,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl- orN,N′-dicyclo-hexylcarbodiimide (DCC) orN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),phosgene derivatives such as N,N′-carbonyldiimidazole (CDI),1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, acylaminocompounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orisobutyl chloroformate, propanephosphonic anhydride, diethylcyanophosphonate, bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride,benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexa-fluorophosphate, benzotriazol-1-yloxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU),2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TPTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU), optionally in combination with other additivessuch as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu),and, as bases, alkali metal carbonates, e.g. sodium or potassiumcarbonate or hydrogen carbonate, or organic bases such astrialkylamines, e.g. triethylamine, N-methylmorpholine,N-methylpiperidine or N,N-diisopropylethylamine. Preferably EDC incombination with HOBt or TBTU in the presence ofN,N-diisopropylethylamine is used.

The condensation (II)+(III)→(I) is generally performed in a temperaturerange from −20° C. to +60° C., preferably at 0° C. to +40° C. Thereaction can take place under standard atmospheric, increased or reducedpressure (e.g. from 0.5 to 5 bar). The operation is generally carriedout under atmospheric pressure.

Inert solvents for the process step (IV)+(V)→(I) are for examplehalogenated hydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, trichloroethylene or chlorobenzene, ethers such asdiethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene,xylene, hexane, cyclohexane or petroleum fractions, or other solventssuch as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile,N,N-dimethylformamide, dimethyl sulphoxide, N,N′-dimethylpropyleneurea(DMPU), N-methyl-pyrrolidone (NMP) or pyridine. Likewise it is possibleto use mixtures of the said solvents. Preferably, acetonitrile, acetoneor dimethylformamide is used.

As bases for the process step (IV)+(V)→(I), the usual inorganic ororganic bases are suitable. These preferably include alkali metalhydroxides such as for example lithium, sodium or potassium hydroxide,alkali metal or alkaline earth metal carbonates such as lithium, sodium,potassium, calcium or caesium carbonate, alkali metal alcoholates suchas sodium or potassium methanolate, sodium or potassium ethanolate orsodium or potassium tert-butylate, alkali metal hydrides such as sodiumor potassium hydride, amides such as sodamide, lithium or potassiumbis(trimethylsilyl)amide or lithium diisopropylamide, or organic aminessuch as triethylamine, N-methylmorpholine, N-methylpiperidine,N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo-[4.3.0]non-5-ene(DBN), 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) or1,4-diazabicyclo[2.2.2]-octane (DABCO®). Preferably, potassium carbonateor caesium carbonate is used.

In this step, the base is used in an amount of 1 to 5 mol, preferably inan amount of 1 to 2.5 mol, based on 1 mol of the compound of the formula(IV). The reaction generally takes place in a temperature range from 0°C. to +100° C., preferably at +20° C. to +80° C. The reaction can takeplace under standard atmospheric, increased or reduced pressure (e.g.from 0.5 to 5 bar). The operation is generally carried out underatmospheric pressure.

The preparation of the compounds of the invention can be illustrated bythe following synthesis scheme:

Alternatively, compounds of the formula (I) in which A is —CH₂— or—CH₂—CH₂— can also be prepared by reducing a compound of the formula(XV)

in which Q, R¹, R², R⁴, R⁵ and R²⁹ are each as defined above andT¹ is hydrogen or (C₁-C₄)-alkyl,in an inert solvent in the presence of a suitable reducing agent, togive a compound of the formula (I-A)

in which Q, R¹, R², R⁴, R⁵ and R²⁹ are each as defined above,and subjecting the compound (I-A), if desired, to further modificationin accordance with the reactions and methods known to a person skilledin the art, such as, for example, nucleophilic and electrophilicsubstitutions, oxidations, reductions, hydrogenations, transitionmetal-catalysed coupling reactions, eliminations, alkylation, amination,esterification, ester cleavage, etherification, ether cleavage, and alsointroduction and removal of temporary protecting groups.

Suitable inert solvents for the process step (XV)→(I-A) here arealcohols such as methanol, ethanol, n-propanol or isopropanol, or etherssuch as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether,dimethoxyethane or diethylene glycol dimethyl ether, or halogenatedhydrocarbons such as dichloromethane, trichloromethane, carbontetrachloride or 1,2-dichloroethane, or other solvents such asdimethylformamide. It is likewise possible to use mixtures of the saidsolvents. Preference is given to using dimethoxyethane andtetrahydrofuran.

Suitable reducing agents for the process step (XV)→(I-A) includeborohydrides, such as, for example, sodium borohydride, sodiumtriacetoxyborohydride, lithium borohydride or sodium cyanoborohydride,aluminium hydrides such as, for example, lithium aluminium hydride,sodium bis(2-methoxyethoxy)aluminium hydride or diisobutylaluminiumhydride, diborane or borane-tetrahydrofuran complex.

The reaction (XV)→(I-A) takes place in general in a temperature rangefrom 0° C. to +60° C., preferably from 0° C. to +40° C.

The compounds of the formula (II) can be obtained by base-inducedalkylation of compounds of the formula (IV) to give the N²-substitutedcompounds (VII) and subsequent ester hydrolysis (see Scheme 2):

The compounds of the formula (VII) in which Q is N may alternativelyalso be prepared from N-(alkoxycarbonyl)arylthioamides of the formula(IX), which are known from the literature [see, for example, M.Arnswald, W. P. Neumann, J. Org. Chem. 58 (25), 7022-7028 (1993); E. P.Papadopoulos, J. Org. Chem. 41 (6), 962-965 (1976)], by reaction withhydrazino esters of the formula (VIII) and subsequent alkylation at N−4of the triazolone (X) (Scheme 3):

The compounds of the formula (IV) in which Q is N may be preparedstarting from carboxylic hydrazides of the formula (XI) by reaction withisocyanates of the formula (XII) or nitrophenyl carbamates of theformula (XIII) and subsequent base-induced cyclisation of theintermediate hydrazinecarboxamides (XIV) (Scheme 4):

The compound in which R¹ corresponds to the substituent CH₂CH(OH)CF₃ isreacted, initially following Scheme 4, from alkyl isocyanatoacetate(XIIa) and (XI) to give (XIVa). Subsequent basic cyclisation leads tothe triazolone (IVa). Introduction of the CF₃ group is accomplished byreaction of (IVa) with trifluoroacetic anhydride in pyridine. Theresulting ketone (IVb) can then be converted by reduction to (IVc)(Scheme 5):

The compounds of the formula (II) in which Q is CH are accessiblethrough reaction of α-amino ketones of the formula (XVI) withisocyanates of the formula (XVII) and subsequent ester hydrolysis(Scheme 6). The compounds of the formula (XVI), for their part, can besynthesized in a way which is known from the literature, from α-bromoketones of the formula (XVIII) and amino esters of the formula (XIX)(Scheme 7):

The compounds of the formulae (III), (V), (VI), (VIII), (IX), (XI),(XII), (XIIa), (XIII), (XVII), (XIX) and (XX) are variously availablecommercially, known from the literature, or can be prepared in analogyto processes known from the literature, or as described in the presentexperimental section.

Further compounds of the invention may also be prepared, if desired, byconversions of functional groups of individual substituents,particularly those listed under R¹ and R³, starting from the compoundsof the formula (I) obtained in accordance with processes above. Theseconversions are carried out in accordance with customary methods knownto a person skilled in the art, and include, for example, reactions suchas nucleophilic and electrophilic substitutions, oxidations, reductions,hydrogenations, transition metal-catalysed coupling reactions,eliminations, alkylation, amination, esterification, ester cleavage,etherification, ether cleavage, especially formation of carboxamides,and also introduction and removal of temporary protecting groups.

The present invention further encompasses compounds of the formula (III)

in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen or trifluoromethyl,    -   R^(6B) is hydrogen,    -   R^(7A) is hydrogen,    -   R^(7B) is hydrogen,-   Q is N,-   R³ is hydroxyl, amino, —NR⁸—C(═O)—R⁹, —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³,    —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸, —NR¹⁹—C(═O)—OR²⁰,    —S(═O)_(n)R²¹ or —NR²⁶—SO₂—NR²⁷R²⁸—,    -   where    -   R⁸ is hydrogen,    -   R⁹ is methyl,    -   R¹⁰ is hydrogen,    -   R¹¹ is methyl or ethyl,    -   R¹² is methyl,    -   R¹³ is methyl,    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,    -   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl,    -   or    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 2-oxoimidazolidin-1-yl or a        2-oxotetrahydropyrimidin-1(2H)-yl ring,    -   R¹⁹ is hydrogen,    -   R²⁰ is methyl or ethyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl        ring,    -   n is a number 0 or 2,    -   R²¹ is methyl,    -   R²⁶ is hydrogen,    -   R²⁷ is hydrogen,    -   R²⁸ is hydrogen,-   R⁴ is a group of the formula

-   -   where    -   # is the attachment site to —C(R⁵)(AR³)N—,    -   R²² is hydrogen, fluorine, chlorine and trifluoromethyl,    -   R²³ is hydrogen, fluorine, chlorine and trifluoromethyl,    -   where at least one of the radicals R²² and R²³ is other than        hydrogen,

-   R⁵ is hydrogen or methyl,

-   R²⁹ is hydrogen.

The present invention further encompasses compounds of the formula (V)

in which

-   A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,)    -   where    -   * is the attachment site to R³,    -   R^(6A) is hydrogen or trifluoromethyl,    -   R^(6B) is hydrogen,    -   R^(7A) is hydrogen,    -   R^(7B) is hydrogen,-   Q is N,-   R³ is hydroxyl, amino, —NR⁸—C(═O)—R⁹, —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³,    —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸, —NR¹⁹—C(═O)—OR²⁰,    —S(═O)_(n)R²¹ or —NR²⁶—SO₂—NR²⁷R²⁸—,    -   where    -   R⁸ is hydrogen,    -   R⁹ is methyl,    -   R¹⁰ is hydrogen,    -   R¹¹ is methyl or ethyl,    -   R¹² is methyl,    -   R¹³ is methyl,    -   R¹⁴ is hydrogen or methyl,    -   R¹⁵ is hydrogen, methyl or ethyl,    -   R¹⁶ is hydrogen,-   R¹⁷ is hydrogen or methyl,    -   R¹⁸ is hydrogen, methyl or ethyl,    -   or    -   R¹⁶ and R¹⁷ together with the nitrogen atoms to which they are        attached form a 2-oxoimidazolidin-1-yl or a        2-oxotetrahydropyrimidin-1(2H)-yl ring,    -   R¹⁹ is hydrogen,    -   R²⁰ is methyl or ethyl,    -   or    -   R¹⁹ and R²⁰ together with the atoms to which they are attached        form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl        ring,    -   n is a number 0 or 2,    -   R²¹ is methyl,    -   R²⁶ is hydrogen,    -   R²⁷ is hydrogen,    -   R²⁸ is hydrogen,-   R⁴ is a group of the formula

-   -   where    -   # is the attachment site to —C(R⁵)(AR³)N—,    -   R²² is hydrogen, fluorine, chlorine and trifluoromethyl,    -   R²³ is hydrogen, fluorine, chlorine and trifluoromethyl,    -   where at least one of the radicals R²² and R²³ is other than        hydrogen,

-   R⁵ is hydrogen or methyl,

-   R²⁹ is hydrogen.

The present invention further encompasses the following compound:

-   5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one.

The compounds according to the invention possess valuablepharmacological properties and can be used for the prevention and/ortreatment of various diseases and disease-induced states in humans andanimals.

The compounds according to the invention are potent selective dualV1a/V2 receptor antagonists, which inhibit vasopressin activity in vitroand in vivo.

The compounds according to the invention are particularly suitable forthe prophylaxis and/or treatment of cardiovascular diseases. In thisconnection, the following may for example and preferably be mentioned astarget indications: acute and chronic cardiac insufficiency, arterialhypertension, coronary heart disease, stable and unstable anginapectoris, myocardial ischaemia, myocardial infarction, shock,arteriosclerosis, atrial and ventricular arrhythmias, transitory andischaemic attacks, stroke, inflammatory cardiovascular diseases,peripheral and cardiac vascular diseases, peripheral circulationdisorders, arterial pulmonary hypertension, spasms of the coronaryarteries and peripheral arteries, thromboses, thromboembolic diseases,oedema formation such as for example pulmonary oedema, cerebral oedema,renal oedema or cardiac insufficiency-related oedema, and restenoses forexample after thrombolysis treatments, percutaneous-transluminalangioplasties (PTA), transluminal coronary angioplasties (PTCA), hearttransplants and bypass operations.

In the sense of the present invention, the term cardiac insufficiencyalso includes more specific or related disease forms such as rightcardiac insufficiency, left cardiac insufficiency, global insufficiency,ischaemic cardiomyopathy, dilatative cardiomyopathy, congenital heartdefects, heart valve defects, cardiac insufficiency with heart valvedefects, mitral valve stenosis, mitral valve insufficiency, aortic valvestenosis, aortic valve insufficiency, tricuspidal stenosis, tricuspidalinsufficiency, pulmonary valve stenosis, pulmonary valve insufficiency,combined heart valve defects, heart muscle inflammation (myocarditis),chronic myocarditis, acute myocarditis, viral myocarditis, diabeticcardiac insufficiency, alcohol-toxic cardiomyopathy, cardiac storagediseases, diastolic cardiac insufficiency and systolic cardiacinsufficiency.

Furthermore, the compounds according to the invention are suitable foruse as a diuretic for the treatment of oedemas and in electrolytedisorders, in particular in hypervolaemic and euvolaemic hyponatraemia.

The compounds according to the invention are also suitable for theprophylaxis and/or treatment of polycystic kidney disease (PCKD) andsyndrome of inappropriate ADH secretion (SIADH).

In addition, the compounds according to the invention can be used forthe prophylaxis and/or treatment of liver cirrhosis, ascites, diabetesmellitus and diabetic complications such as for example neuropathy andnephropathy, acute and chronic kidney failure and chronic renalinsufficiency.

Further, the compounds according to the invention are suitable for theprophylaxis and/or treatment of central nervous disorders such asanxiety states and depression, of glaucoma and of cancer, in particularof pulmonary tumours.

Furthermore, the compounds according to the invention can be used forthe prophylaxis and/or treatment of inflammatory diseases, asthmaticdiseases, chronic-obstructive respiratory tract diseases (COPD), painconditions, prostatic hypertrophy, incontinence, bladder inflammation,hyperactive bladder, diseases of the adrenals such as for examplephaeochromocytoma and adrenal apoplexy, diseases of the intestine suchas for example Crohn's disease and diarrhoea, or of menstrual disorderssuch as for example dysmenorrhoea, or endometriosis.

A further object of the present invention is the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofdiseases, in particular of the diseases mentioned above.

A further object of the present invention are the compounds according tothe invention for use in a method for the treatment and/or prophylaxisof acute and chronic cardiac insufficiency, hypervolaemic and envolaemichyponatraemia, liver cirrhosis, ascites, oedemas, and the syndrome ofinadequate ADH secretion (SIADH).

A further object of the present invention is the use of the compoundsaccording to the invention for the production of a medicament for thetreatment and/or prophylaxis of diseases, in particular of the diseasesmentioned above.

A further object of the present invention is a method for the treatmentand/or prophylaxis of diseases, in particular of the diseases mentionedabove, with the use of an effective quantity of at least one of thecompounds according to the invention.

The compounds according to the invention can be used alone or ifnecessary in combination with other active substances. A further objectof the present invention are medicaments which contain at least one ofthe compounds according to the invention and one or more other activesubstances, in particular for the treatment and/or prophylaxis of thediseases mentioned above. As combination active substances suitable forthis, the following may for example and preferably be mentioned:

-   -   organic nitrates and NO donors, such as for example sodium        nitroprusside, nitroglycerine, isosorbide mononitrate,        isosorbide dinitrate, molsidomine or SIN-1, and inhalational NO;    -   diuretics, in particular loop diuretics and thiazides and        thiazide-like diuretics;    -   positive-inotropically active compounds, such as for example        cardiac glycosides (digoxin), and beta-adrenergic and        dopaminergic agonists such as isoproterenol, adrenalin,        noradrenalin, dopamine and dobutamine;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), such as for example inhibitors of phosphodiesterases        (PDE) 1, 2, 3, 4 and/or 5, in particular PDE 5 inhibitors such        as sildenafil, vardenafil and tadalafil, and PDE 3 inhibitors        such as aminone and milrinone;    -   natriuretic peptides such as for example “atrial natriuretic        peptide” (ANP, anaritide), “B-type natriuretic peptide” or        “brain natriuretic peptide” (BNP, nesiritide), “C-type        natriuretic peptide” (CNP) and urodilatin;    -   calcium sensitisers, such as for example and preferably        levosimendan;    -   NO- and haem-independent activators of guanylate cyclase, such        as in particular the compounds described in WO 01/19355, WO        01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO        02/070510;    -   NO-independent, but haem-dependent stimulators of guanylate        cyclase, such as in particular riociguat and the compounds        described in WO 00/06568, WO 00/06569, WO 02/42301 and WO        03/095451;    -   inhibitors of human neutrophil elastase (HNE), such as for        example sivelestat or DX-890 (reltran);    -   compounds inhibiting the signal transduction cascade, such as        for example tyrosine kinase inhibitors, in particular sorafenib,        imatinib, gefitinib and erlotinib;    -   compounds influencing the energy metabolism of the heart, such        as for example and preferably etomoxir, dichloracetate,        ranolazine or trimetazidine;    -   agents with antithrombotic action, for example and preferably        from the group of the thrombo-cyte aggregation inhibitors,        anticoagulants or profibrinolytic substances;    -   blood pressure-lowering active substances, for example and        preferably from the group of the calcium antagonists,        angiotensin AII antagonists, ACE inhibitors, vasopeptidase        inhibitors, inhibitors of neutral endopeptidase, endothelin        antagonists, renin inhibitors, alpha receptor blockers, beta        receptor blockers, mineralocorticoid receptor antagonists and        rho-kinase inhibitors; and/or    -   active substances modifying fat metabolism, for example and        preferably from the group of the thyroid receptor agonists,        cholesterol synthesis inhibitors such as for example and        preferably HMG-CoA reductase or squalene synthesis inhibitors,        ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha,        PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption        inhibitors, lipase inhibitors, polymeric gallic acid adsorbers,        gallic acid reabsorption inhibitors and lipoprotein(a)        antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, such asfor example and preferably furosemid, bumetanid, torsemid,bendroflumethiazid, chlorthiazid, hydrochlorthiazid, hydroflumethiazid,methyclothiazid, polythiazid, trichlormethiazid, chlorthalidon,indapamid, metolazon, quinethazon, acetazolamid, dichlorophenamid,methazolamid, glycerine, isosorbide, mannitol, amilorid or triamteren.

Agents with antithrombotic action are understood preferably to meancompounds from the group of the thrombocyte aggregation inhibitors,anticoagulants or profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombocyteaggregation inhibitor, such as for example and preferably aspirin,clopidogrel, ticlopidine or dipyridamol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitor,such as for example and preferably ximela-gatran, melagatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist, such as for example and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xainhibitor, such as for example and preferably riva-roxaban (BAY59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban,fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982,MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist, such as for example and preferably coumarin.

Blood pressure-lowering agents are understood preferably to meancompounds from the group of the calcium antagonists, angiotensin AIIantagonists, ACE inhibitors, vasopeptidase inhibitors, inhibitors ofneutral endopeptidase, endothelin antagonists, renin inhibitors, alphareceptor blockers, beta receptor blockers, mineralocorticoid receptorantagonists, rho-kinase inhibitors and diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,such as for example and preferably nife-dipin, amlodipin, verapamil ordiltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIantagonist, such as for example and preferably losartan, candesartan,valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor,such as for example and preferably enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vasopeptidaseinhibitor or inhibitor of neutral endopeptidase (NEP).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist, such as for example and preferably bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitor,such as for example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1 receptorblocker, such as for example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta receptorblocker, such as for example and preferably propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist, such as for example and preferably spironolactone,eplerenon, canrenon or potassium canrenoate.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a rho-kinaseinhibitor, such as for example and preferably fasu-dil, Y-27632,SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

Fat metabolism-modifying agents are understood preferably to meancompounds from the group of the CETP inhibitors, thyroid receptoragonists, cholesterol synthesis inhibitors such as HMG-CoA reductase orsqualene synthesis inhibitors, ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric gallic acid adsorbers, gallic acidreabsorption inhibitors, lipase inhibitors and lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor,such as for example and preferably dalcetrapib, BAY 60-5521, anacetrapibor CETP-vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist, such as for example and preferably D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of the statins, such as for example andpreferably lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor, such as for example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitor,such as for example and preferably avasi-mibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor,such as for example and preferably implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonist,such as for example and preferably pio-glitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonist,such as for example and preferably GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, such as for example and preferably ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor,such as for example and preferably orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric gallicacid adsorber, such as for example and preferably cholestyramine,colestipol, colesolvam, cholestagel or colestimid.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a gallic acidreabsorption inhibitor, such as for example and preferably ASBT(=IBAT)inhibitors such as for example AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein(a)antagonist, such as for example and preferably gemcabene calcium(CI-1027) or nicotinic acid.

A further object of the present invention are medicaments which containat least one compound according to the invention, usually together withone or more inert, non-toxic, pharmaceutically suitable additives, andthe use thereof for the aforesaid purposes.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, such as for example by the oral, parenteral, pulmonary, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor aural routes or as an implant or stent.

For these administration routes, the compounds according to theinvention can be administered in suitable administration forms.

For oral administration, administration forms which function accordingto the state of the art, releasing the compounds according to theinvention rapidly and/or in a modified manner, which contain thecompounds according to the invention in crystalline and/or amorphizedand/or dissolved form, such as for example tablets (uncoated or coatedtablets, for example with gastric juice-resistant or delayed dissolutionor insoluble coatings, which control the release of the compoundaccording to the invention), tablets rapidly disintegrating in the oralcavity or films/wafers, films/lyophilisates, capsules (for example hardor soft gelatine capsules), dragees, granules, pellets, powders,emulsions, suspensions, aerosols or solutions are suitable.

Parenteral administration can be effected omitting an absorption step(e.g. intravenous, intra-arterial, intracardial, intraspinal orintralumbar administration) or involving absorption (e.g.intra-muscular, subcutaneous, intracutaneous, percutaneous orintraperitoneal administration). Suitable administration forms forparenteral administration include injection and infusion preparations inthe form of solutions, suspensions, emulsions, lyophilisates or sterilepowders.

For the other administration routes, for example inhalation formulations(including powder inhalers and nebulisers), nasal drops, solutions orsprays, tablets for lingual, sublingual or buccal administration,tablets, films/wafers or capsules, suppositories, oral or ophthalmicpreparations, vaginal capsules, aqueous suspensions (lotions, shakablemixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. plasters), milk, pastes, foams, dustingpowders, implants or stents are suitable.

Oral or parenteral administration, in particular oral and intravenousadministration, are preferred.

The compounds according to the invention can be converted into thestated administration forms. This can be effected in a manner known perse by mixing with inert, non-toxic, pharmaceutically suitable additives.These additives include carriers (for example microcrystallinecellulose, lactose, mannitol), solvents (e.g. liquid polyethyleneglycols), emulsifiers and dispersants or wetting agents (for examplesodium dodecylsulphate, polyoxysorbitan oleate), binders (for examplepolyvinylpyrrolidone), synthetic and natural polymers (for examplealbumin), stabilizers (e.g. antioxidants such as for example ascorbicacid), colourants (e.g. inorganic pigments such as for example ironoxides) and flavour or odour correctors.

In general, to achieve effective results in parenteral administration ithas been found advantageous to administer quantities of about 0.001 to10 mg/kg, preferably about 0.01 to 1 mg/kg body weight. In oraladministration, the dosage is about 0.01 bis 100 mg/kg, preferably about0.01 to 20 mg/kg and quite especially preferably 0.1 to 10 mg/kg bodyweight.

Nonetheless it can sometimes be necessary to deviate from the saidquantities, namely depending on body weight, administration route,individual response to the active substance, nature of the preparationand time or interval at which administration takes place. Thus in somecases it can be sufficient to manage with less than the aforesaidminimum quantity, while in other cases the stated upper limit must beexceeded. In the event of administration of larger quantities, it may beadvisable to divide these into several individual administrationsthrough the day.

The following practical examples illustrate the invention. The inventionis not limited to the examples.

Unless otherwise stated, the percentages stated in the following testsand examples are percent by weight, parts are parts by weight, andsolvent ratios, dilution ratios and concentration information aboutliquid/liquid solutions are each based on volume.

A. EXAMPLES Abbreviations

-   BOC tert-butoxycarbonyl-   CI chemical ionization (in MS)-   DCI direct chemical ionization (in MS)-   DME 1,2-dimethoxyethane-   DMF dimethylformamide-   DMSO dimethyl sulphoxide-   EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride-   eq. equivalent(s)-   ESI electrospray ionization (in MS)-   GC/MS gas chromatography-coupled mass spectrometry-   sat. saturated-   h hour(s)-   HOBt 1-hydroxy-1H-benzotriazole hydrate-   HPLC high pressure, high performance liquid chromatography-   HV high vacuum-   LC/MS liquid chromatography-coupled mass spectrometry-   LDA lithium diisopropylamide-   LiHMDS lithium hexamethyldisilazane min(s) minute(s)-   MS mass spectrometry-   MTBE methyl tert-butyl ether-   NMR nuclear magnetic resonance spectrometry rac racemic/racemate-   R_(f) retention factor (in thin layer chromatography on silica gel)-   RT room temperature-   R_(t) retention time (in HPLC)-   THF tetrahydrofuran-   TMOF trimethyl orthoformate-   UV ultraviolet spectrometry-   v/v volume to volume ratio (of a solution)

LC/MS, HPLC and GC/MS Methods:

Method 1: MS instrument type: Micromass ZQ; HPLC instrument type: WatersAlliance 2795; column: Phenomenex Synergi 2.5μ MAX-RP 100A Mercury 20mm×4 mm; eluent A: 11 water+0.5 ml 50% formic acid, eluent B: 11acetonitrile+0.5 ml 50% formic acid; gradient: 0.0 min 90% A→0.1 min 90%A→3.0 min 5% A→4.0 min 5% A→4.01 min 90% A; flow rate: 2 ml/min; oven:50° C.; UV detection: 210 nm.

Method 2: MS instrument type: Waters (Micromass) Quattro Micro; HPLCinstrument type: Agilent 1100 series; column: Thermo Hypersil GOLD 3μ20×4 mm; eluent A: 11 water+0.5 ml 50% formic acid; eluent B: 11acetonitrile+0.5 ml 50% formic acid; gradient: 0.0 min 100% A→3.0 min10% A→4.0 min 10% A→4.01 min 100% A (flow 2.5 ml)→5.00 min 100% A; oven:50° C.; flow rate: 2 ml/min; UV detection: 210 nm.

Method 3: Instrument: Micromass Quattro Premier with Waters HPLCAcquity; column: Thermo Hypersil GOLD 1.9μ 50×1 mm; eluent A: 11water+0.5 ml 50% formic acid, eluent B: 11 acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 min 90% A→0.1 min 90% A→15 min 10% A→2.2 min10% A; oven: 50° C.; flow rate: 0.33 ml/min; UV detection: 210 nm.

Method 4: Instrument: Waters ACQUITY SQD HPLC System; column: WatersAcquity HPLC HSS T3 1.8μ 50×1 mm; eluent A: 11 water+0.25 ml 99% formicacid; eluent B: 11 acetonitrile+0.25 ml 99% formic acid; gradient: 0.0min 90% A→1.2 min 5% A→2.0 min 5% A; oven: 50° C.; flow rate: 0.40ml/min; UV detection: 210-400 nm.

Method 5: Instrument: Waters ACQUITY SQD HPLC System; column: WatersAcquity HPLC HSS T3 1.8μ 50×1 mm; eluent A: 11 water+0.25 ml 99% formicacid; eluent B: 11 acetonitrile+0.25 ml 99% formic acid; gradient: 0.0min 90% A→1.2 min 5% A→2.0 min 5% A; oven: 50° C.; flow rate: 0.40ml/min; UV detection: 210-400 nm.

Method 6: MS instrument type: Micromass ZQ; HPLC instrument type: HP1100 Series; UV DAD; column: Phenomenex Gemini 3μ 30 mm×3.00 mm; eluentA: 11 water+0.5 ml 50% formic acid; eluent B: 11 acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min5% A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min;oven: 50° C.; UV detection: 210 nm.

Method 7: MS instrument type: Waters ZQ; HPLC instrument type: Agilent1100 Series; UV DAD; column: Thermo Hypersil GOLD 3μ 20 mm×4 mm; eluentA: 11 water+0.5 ml 50% formic acid; eluent B: 11 acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10% A→4.1min 100% flow rate: 2.5 ml/min; oven: 55° C.; flow rate 2 ml/min; UVdetection: 210 nm.

Method 8 (chiral preparative HPLC): Chiral stationary silica gel phasebased on the selectorpoly-(N-methacryloyl-D-leucine-dicyclopropylmethylamide); column: 670mm×40 mm, flow rate: 80 ml/min, temperature: 24° C.; UV detector 260 nm.Eluent: isohexane/ethyl acetate 30:70.

Method 8a: Eluent: isohexane/ethyl acetate 10:90 (v/v); flow rate: 50ml/min

Method 9 (chiral analytical HPLC): Chiral stationary silica gel phasebased on the selectorpoly(N-methacryloyl-D-leucine-dicyclopropylmethylamide); column: 250mm×4.6 mm, eluent ethyl acetate 100%, flow rate: 1 ml/min, temperature:24° C.; UV detector 265 nm.

Method 10 (preparative HPLC): column: Grom-Sil 1200DS-4HE, 10 μm, SNo.3331, 250 mm×30 mm Eluent A: formic acid 0.1% in water, eluent B:acetonitrile; flow rate: 50 ml/min programme: 0-3 min: 10% B; 3-27 min:gradient to 95% B; 27-34 min: 95% B; 34.01-38 min: 10% B.

Method 11 (chiral preparative HPLC): Stationary phase Daicel ChiralcelOD-H, 5 μm, column: 250 mm×20 mm; temperature: RT; UV detection: 230 nm.Various eluents:

Method 11a: Eluent: isohexane/isopropanol 70:30 (v/v); flow rate: 20ml/min

Method 11b: Eluent: isohexane/isopropanol 50:50 (v/v); flow rate: 18ml/min

Method 11c: Eluent: isohexane/methanol/ethanol 70:15:15; (v/v/v); flowrate 20 ml/min

Method 11d: Eluent: isohexane/isopropanol 75:25 (v/v); flow rate 15ml/min

Method 12 (chiral analytical HPLC): Stationary phase Daicel ChiralcelOD-H, column: 250 mm×4 mm; flow rate: 1 ml/min; temperature: RT; UVdetection: 230 nm. Various eluents:

Method 12a: Eluent: isohexane/isopropanol 1:1 (v/v);

Method 12b: Eluent: isohexane/methanol/ethanol 70:15:15 (v/v/v)

Method 12c: Eluent: isohexane/isopropanol 75:25 (v/v);

Method 13 (chiral preparative HPLC): Chiral stationary silica gel phasebased on the selectorpoly-(N-methacryloyl-D-leucine-dicyclopropylmethylamide); column: 600mm×30 mm, eluent: step gradient ethyl acetate/methanol 1:1 (0-17 min)ethyl acetate (17.01 min to 21 min) ethyl acetate/methanol 1:1 (21.01min to 25 min); flow rate: 80 ml/min, temperature: 24° C.; UV detector265 nm.

Method 13a: as Method 13, but eluent: 0-5.08 min isohexane/ethyl acetate10:90, then ethyl acetate 100%

Method 13b: Eluent: 100% ethyl acetate

Method 14 (chiral analytical HPLC): as Method 9 but flow rate 2 ml/min.

Method 15 (chiral preparative HPLC): Chiral stationary silica gel phasebased on the selector poly(N-methacryloyl-L-isoleucine-3-pentylamide);column: 430 mm×40 mm, flow rate: 80 ml/min, temperature: 24° C.; UVdetector 265 nm. Various eluents:

Method 15a: 100% ethyl acetate

Method 15b: isohexane/ethyl acetate 10:90

Method 16 (chiral analytical HPLC): Chiral stationary silica gel phasebased on the selector poly(N-methacryloyl-L-isoleucine-3-pentylamide);column: 250 mm×4.6 mm, eluent 100% ethyl acetate, flow rate: 2 ml/min,temperature: 24° C.; UV detector 265 nm.

Method 17 (chiral preparative HPLC): Chiral stationary silica gel phasebased on the selectorpoly(N-methacryloyl-L-leucine-(+)-3-pinanemethylamide); column: 600mm×30 mm, flow rate: 80 ml/min, temperature: 24° C.; UV detector 265 nm.Various eluents:

-   -   Method 17a: isohexane/ethyl acetate 20:80    -   Method 17b: isohexane/ethyl acetate 30:70    -   Method 17c: isohexane/ethyl acetate 50:50    -   Method 17d: 100% ethyl acetate    -   Method 17e: isohexane/ethyl acetate 40:60    -   Method 17f: isohexane/ethyl acetate 10:90

Method 18 (chiral analytical HPLC): Chiral stationary silica gel phasebased on the selectorpoly(N-methacryloyl-L-leucine-(+)-3-pinanemethylamide); column: 250mm×4.6 mm, temperature: 24° C.; UV detector 265 nm.

Method 18a: Eluent: isohexane/ethyl acetate 50:50, flow rate: 2 ml/min.

Method 18b: Eluent: 100% ethyl acetate, flow rate: 2 ml/min.

Method 18c: Eluent: 100% ethyl acetate, flow rate: 1 ml/min.

Method 19 (preparative HPLC): column Grom-Sil 1200DS-4HE 10 μm, 250mm×30 mm; eluent: A=water, B=acetonitrile; gradient: 0.0 min 10% B, 3min 10% B, 30 min 95% B, 42 min 95% B, 42.01 min 10% B, 45 min 10% B;flow rate: 50 ml/min; column temperature: RT; UV detection: 210 nm.

Method 20 (preparative HPLC): column: Reprosil C18, 10 μm, 250 mm×30 mmEluent A: formic acid 0.1% in water, eluent B: methanol; flow rate: 50ml/min Programme: 0 to 4.25 min: 90% A/10% B; 4.26-4.5 min: Gradient to60% B; 4.5-11.5 min: gradient to 80% B; 11.51-17 min gradient to 100% B;17.01 to 19.5 min 100% B; 19.51-19.75 gradient to 40% B; 19.76 to 20.51min: 60% A/40% B.

Method 21 chiral preparative HPLC): Stationary phase Daicel ChiralpakAS-H, 5 μm, column: 250 mm×20 mm; temperature: RT; UV detection: 230 nm;flow rate: 20 ml/min; various eluents:

Method 21a: Eluent: isohexane/isopropanol 65:35

Method 21b: Eluent: isohexane/isopropanol 50:50; flow rate 20 ml/min

Method 22 (chiral analytical HPLC): Stationary phase Daicel ChiralpakAD-H 5 μm, column: 250 mm×4 mm; UV detection: 220 nm. Flow rate: 1ml/min. Eluent: isohexane/isopropanol 50:50.

Method 23 (preparative HPLC): column: YMC ODS C18, 10 μm, 250 mm×30 mmEluent A: formic acid 0.1% in water, eluent B: methanol; flow rate: 50ml/min. Programme: 0 to 4.25 min: 90% A/10% B; 4.26-4.5 min: gradient to60% B; 4.5-11.5 min: gradient to 80% B; 11.51-17 min gradient to 100% B;17.01 to 19.5 min 100% B; 19.51-19.75 gradient to 40% B; 19.76 to 20.51min: 60% A/40% B.

Method 24 (chiral preparative HPLC): Chiral stationary phase based onthe selector poly(N-methacryloyl-L-leucine-tert-butylamide) on irregular(fractionated) vinyl silica gel column: 250 mm×20 mm, flow rate: 45ml/min, temperature: RT; UV detector 260 nm. Various eluents:

Method 24a: isohexane/ethyl acetate 10:90

Method 24b: isohexane/ethyl acetate 20:80

Method 25 (chiral analytical HPLC): Chiral stationary phase based on theselector poly(N-methacryloyl-L-leucine-tert-butylamide) on irregular(fractionated) vinyl silica gel column: 250 mm×4 mm, flow rate: 1.5ml/min, temperature: RT; UV detector 260 nm. Various eluents:

Method 25a: isohexane/ethyl acetate 20:80

Method 25b: isohexane/ethyl acetate 30:70

Method 26 (chiral preparative HPLC): Stationary phase Daicel ChiralpakAD-H, 5 μm, column: 250 mm×20 mm; temperature: RT; UV detection: 230 nm;flow rate: 20 ml/min; various eluents.

Method 26a: isohexane/isopropanol 65:35 (v/v)

Method 26b: isohexane/isopropanol 80:20 (v/v)

Method 26c: isohexane/isopropanol 50:50 (v/v)

Method 26d: isohexane/ethanol 65:35 (v/v)

Method 26e: isohexane/ethanol 50:50 (v/v)

Method 27 (chiral analytical HPLC): Stationary phase Daicel ChiralpakAD-H, 5 μm, column: 250 mm×4 mm; temperature: 30° C.; UV detection: 230nm; flow rate: 1 ml/min; various eluents.

Method 27a: isohexane/isopropanol 50:50 (v/v)

Method 27b: isohexane/isopropanol 60:40 (v/v)

Method 27c: isohexane/isopropanol/20% trifluoroacetic acid 75:24:1(v/v/v)

Method 27d: isohexane/ethanol 50:50 (v/v)

Method 28 chiral preparative HPLC): Chiral stationary silica gel phasebased on the selectorpoly(N-methacryloyl-L-leucine-(+)-3-pinanemethylamide); column: 600mm×40 mm; temperature: RT; UV detector 265 nm; eluent:isohexane/isopropanol 80:20 (v/v); flow rate: 50 ml/min.

Method 29 (chiral preparative HPLC): Chiral stationary phase based onthe selector poly(N-methacryloyl-D-valine-3-pentylamide) on sphericalmercapto silica gel; column: 250 mm×20 mm; temperature: RT; UV detector260 nm; eluent: isohexane/isopropanol 60:40 (v/v); flow rate: 20 ml/min.

Method 30 (chiral preparative HPLC): Chiral stationary phase based onthe selector poly(N-methacryloyl-D-valine-3-pentylamide) on sphericalmercapto silica gel; column: 250 mm×4 mm; temperature: RT; UV detector260 nm; eluent: isohexane/isopropanol 60:40 (v/v); flow rate: 1.5ml/min.

Method 31 (LC-MS): MS instrument type: Waters ZQ; HPLC instrument type:Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3μ 20 mm×4 mm;eluent A: 11 water+0.5 ml 50% formic acid; eluent B: 11 acetonitrile+0.5ml 50% formic acid; gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10%A→4.1 min 100% flow rate: 2.5 ml/min; oven: 55° C.; flow rate 2 ml/min;UV detection: 210 nm.

Method 32 (preparative HPLC): column: Reprosil C18, 10 μm, 250 mm×40 mmEluent A: formic acid 0.1% in water, eluent B: acetonitrile; flow rate:50 ml/min Programme: 0-6 min: 90% A/10% B; 6-40 min: Gradient to 95% B;40-53 min: 5% A/95% B; 53.01-54 min: gradient to 10% B; 54.01-57 min:90% A/10% B.

Method 33 (chiral preparative HPLC): Chiral stationary phase based onthe selector poly(N-methacryloyl-D-leucine-dicyclopropylmethylamide) onspherical vinyl silica gel; column: 670 mm×40 mm, flow rate: 80 ml/min,temperature: 24° C.; UV detector 265 nm. Eluent: 0 to 7.75 min: 100%ethyl acetate; 7.76 min to 12.00 min: 100% methanol; 12.01 min to 16.9min: 100% ethyl acetate.

Method 34: chiral analytical HPLC under SFC (Supercritical FluidChromatography) conditions: chiral stationary phase based on theselector poly(N-methacryloyl-D-leucine-dicyclopropylmethylamide) onspherical vinyl silica gel; column: 250 mm×4.6 mm, temperature: 35° C.,eluent: CO₂/methanol 67:33. Pressure: 120 bar, flow rate: 4 ml/min, UVdetector 250 nm.

Starting Compounds and Intermediates Example 1A EthylN-({2-[(4-chlorophenyl)carbonyl]hydrazinyl}carbonyl)glycinate

A suspension of 12.95 g (75.9 mmol) of 4-chlorobenzhydrazide in 50 ml ofdry THF was introduced at 50° C. and admixed dropwise with a solution of10.0 g (77.5 mmol) of ethyl 2-isocyanatoacetate in 100 ml of dry THF.First of all a solution formed, and then a precipitate was produced.After the end of the addition, the mixture was stirred at 50° C. for 2 hmore, then left to stand overnight at RT. The crystals were isolated byfiltration, washed with a little diethyl ether and dried in an HV. Thisgave 21.43 g (89% of theory) of the title compound.

LC/MS [Method 1]: R_(t)=1.13 min; m/z=300 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=10.29 (s, 1H), 8.21 (s, 1H), 7.91 (d, 2H),7.57 (d, 2H), 6.88 (br.s, 1H), 4.09 (q, 2H), 3.77 (d, 2H), 1.19 (t, 3H)

Example 2A[3-(4-Chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]acetic acid

Of the compound from Example 1A, 21.43 g (67.93 mmol) were admixed with91 ml of a 3N aqueous sodium hydroxide solution and heated at refluxovernight. After cooling to RT, the mixture was adjusted to a pH of 1 byslow addition of approximately 20% strength hydrochloric acid. Theprecipitated solid was isolated by filtration, washed with water anddried at 60° C. under reduced pressure. Yield: 17.55 g (90% of theory,approximately 88% purity).

LC/MS [Method 1]: R_(t)=0.94 min; m/z=254 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=13.25 (br.s, 1H), 12.09 (s, 1H), 7.65-7.56(m, 4H), 4.45 (s, 2H).

Example 3A5-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(or, in hydrate form:5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2,2-dihydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one)

Of the compound from Example 2A, 5 g (16.36 mmol) were dissolved underargon in 200 ml of pyridine and then admixed with 17.18 g (81.8 mmol) oftrifluoroacetic anhydride. The temperature rose to about 35° C. After 30min, the pyridine was removed on a rotary evaporator and the residue wasdiluted with 1.5 l of 0.5N hydrochloric acid. This mixture was heated to70° C. and then filtered while hot. The solid was washed with a littlewater. The entire filtrate was extracted three times with ethyl acetate.The combined organic phases were washed with water, then with asaturated aqueous sodium hydrogen carbonate solution, then with asaturated aqueous sodium chloride solution, dried over sodium sulphateand freed from the solvent on a rotary evaporator. The residue was driedunder HV. Yield: 3.56 g (68% of theory) of the title compound in hydrateform.

LC/MS [Method 1]: R_(t)=1.51 min; m/z=306 (M+H)⁺ and 324 (M+H)⁺(ketoneand hydrate)

¹H NMR (DMSO-d₆, 400 MHz): δ=12.44 (s, 1H), 7.72 (d, 2H), 7.68 (br.s,2H), 7.61 (d, 2H), 3.98 (s, 2H).

Example 4A5-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Of the compound from Example 3A, 3.56 g (11 mmol) were dissolved in 100ml of methanol and admixed, with ice cooling, with 3.75 g (99 mmol) ofsodium borohydride (gas evolution). After 1.5 h, 200 ml of 1Mhydrochloric acid were slowly added. The methanol was removed on arotary evaporator and the residue was diluted with 500 ml of water andextracted three times with ethyl acetate. The combined organic phaseswere washed with saturated aqueous sodium hydrogen carbonate solution,then with saturated aqueous sodium chloride solution, dried over sodiumsulphate and freed from the solvent on a rotary evaporator. The residuewas dried under an HV. This gave 3.04 g (90% of theory) of the titlecompound.

LC/MS [Method 2]: R_(t)=1.80 min; m/z=308 (M+H)⁺.

¹H NMR (DMSO-d₆, 400 MHz): δ=12.11 (s, 1H), 7.75 (d, 2H), 7.62 (d, 2H),6.85 (d, 1H), 4.34-4.23 (m, 1H), 3.92 (dd, 1H), 3.77 (dd, 1H).

Example 5A Methyl[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate

Of the compound from Example 4A, 3.04 g (9.9 mmol) were dissolved in 100ml of acetonitrile and admixed with 1.07 g (9.9 mmol) of methylchloroacetate, 2.73 g (19.8 mmol) of potassium carbonate and a smallspatula-tipful of potassium iodide. The reaction mixture was heated atreflux for 1 h, left to cool to RT and filtered. The filtrate was freedfrom the volatile components on a rotary evaporator and the residue wasdried in an HV. Yield: 3.70 g (89% of theory) of the title compound inapproximately 90% purity.

LC/MS [Method 3]: R_(t)=1.10 min; m/z=380 (M+H)⁺.

¹H NMR (DMSO-d₆, 400 MHz): δ=7.78 (d, 2H), 7.64 (d, 2H), 6.91 (d, 1H),4.72 (s, 2H), 4.16-4.35 (m, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.70 (s,3H).

The racemic compound from Example 5A was resolved by preparative HPLC ona chiral phase into its enantiomers Example 6A and Example 7A, asalready described in WO 2007/134862.

Column: chiral silica gel phase based on the selectorpoly(N-methacryloyl-L-isoleucine-3-pentylamide), 430 mm×40 mm; eluent:step gradient isohexane/ethyl acetate 1:1→ethyl acetate→isohexane/ethylacetate 1:1; flow rate: 50 ml/min; temperature: 24° C.; UV detection:260 nm.

This gives, from 3.6 g of racemic compound from Example 5A (dissolved in27 ml of ethyl acetate and 27 ml of isohexane and separated into threeportions by the column), 1.6 g of the enantiomer 1 which elutes first(Example 6A), and 1.6 g of the enantiomer 2 which elutes subsequently(Example 7A).

Example 6A Methyl{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate(Enantiomer I)

First-eluting enantiomer from the racemate resolution of Example 5A.

R_(t)=3.21 min [column: chiral silica gel phase based on the selectorpoly(N-methacryloyl-L-isoleucine-3-pentylamide), 250 mm×4.6 mm; eluent:isohexane/ethyl acetate 1:1; flow rate: 1 ml/min; UV detection: 260 nm].

Example 7A Methyl{3-(4-chlorophenyl)-5-oxo-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate(Enantiomer II)

Last-eluting enantiomer from the racemate resolution of Example 5A.

R_(t)=4.48 min [column: chiral silica gel phase based on the selectorpoly(N-methacryloyl-L-isoleucine-3-pentylamide), 250 mm×4.6 mm; eluent:isohexane/ethyl acetate 1:1; flow rate: 1 ml/min; UV detection: 260 nm].

Example 8A{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}aceticacid

The enantiomerically pure ester from Example 6A (1.6 g, 4.21 mmol) wasdissolved in 77 ml of methanol and admixed with 17 ml of a 1M solutionof lithium hydroxide in water. The mixture was stirred at RT for 1 h andthen concentrated on a rotary evaporator. The residue was diluted with100 ml of water and acidified to a pH of 1-2 using 1N hydrochloric acid.The precipitated product was isolated by filtration, washed insuccession with water and cyclohexane and sucked dry. After furtherdrying in an HV, the title compound (1.1 g, 71% of theory) was obtained.

[α]_(D) ²⁰=+3.4° (methanol, c=0.37 g/100 ml)

LC/MS [Method 1]: R_(t)=1.51 min; m/z=366 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 4.00 (dd, 1H), 4.25 (m, 1H),4.58 (s, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 13.20 (br. s,1H).

Example 9A{3-(4-Chlorophenyl)-5-oxo-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}aceticacid

In the same way as for Example 8A, the title compound was obtained fromExample 7A.

[α]_(D) ²⁰=−4.6° (methanol, c=0.44 g/100 ml)

LC/MS [Method 1]: R_(t)=1.53 min; m/z=366 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.84 (dd, 1H), 4.00 (dd, 1H), 4.25 (m, 1H),4.58 (s, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 13.20 (br. s,1H).

Example 10A tert-Butyl{(phenylsulphonyl)[3-(trifluoromethyl)phenyl]methyl}carbamate

A quantity of 4.49 g (38.29 mmol) of tert-butyl carbamate and 12.57 g(76.57 mmol) of sodium benzenesulphinate were introduced in 110 ml ofmethanol/water 1:2 and admixed in succession with 10 g (57.43 mmol) of3-(trifluoromethyl)benzenecarbaldehyde and 2.87 ml (76.09 mmol) offormic acid. The mixture was stirred at RT for 30 h. The precipitatedproduct was isolated by filtration, washed in succession with water anddiethyl ether and sucked dry. Further drying in an HV gave 11.2 g (47%of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.86 (d, 1H), 8.14 (s, 1H), 7.99 (d, 1H),7.88 (d, 2H), 7.80 (d, 1H), 7.71-7.77 (m, 1H), 7.59-7.70 (m, 3H), 6.25(d, 1H), 1.18 (s, 9H).

Example 11A tert-Butyl{(E)-[3-(trifluoromethyl)phenyl]methylidene}carbamate

A quantity of 10.88 g (78.73 mmol) of potassium carbonate was dried hotin an HV, left to cool under argon to RT and admixed with 127 ml of THFand also with 5.45 g (13.12 mmol) of the sulphonyl compound from Example10A. The mixture was stirred at reflux for 16 h under argon. The mixturewas cooled to RT and then filtered through Celite. The latter was rinsedwith THF. The entire filtrate was freed from the volatile components ona rotary evaporator and then in an HV, to give 3.63 g (100% of theory)of the title compound.

MS [DCI]: m/z=274 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.95 (s, 1H), 8.26 (s, 1H), 8.23 (d, 1H),8.01 (d, 1H), 7.80 (t, 1H), 1.52 (s, 9H).

Example 12A tert-Butyl{2-nitro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate

Of the compound from Example 11A, 3.6 g (13.17 mmol) were introduced in26 ml of nitromethane and admixed with 0.69 ml (3.95 mmol) ofN,N-diisopropylethylamine. The mixture was stirred at RT for 2 h. Thereaction mixture was diluted with ethyl acetate and washed in successiontwice each with 1N hydrochloric acid and saturated aqueous sodiumhydrogen carbonate solution, and then with saturated aqueous sodiumchloride solution, dried over sodium sulphate and concentrated on arotary evaporator. The residue (about 5 g) was dissolved in 15 ml ofisopropanol at reflux. After cooling, the precipitated product wasisolated by filtration, washed with a little isopropanol and sucked dry.After further drying in an HV, the title compound was obtained: 2.26 g(51% of theory).

LC/MS [Method 3]: R_(t)=1.33 min; ES⁻: m/z=333 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=7.88 (d, 1H), 7.78 (s, 1H), 7.70 (t, 2H),7.59-7.65 (m, 1H), 5.31-5.44 (m, 1H), 4.97 (dd, 1H), 4.72-4.82 (m, 1H),1.36 (s, 9H).

Example 13A 2-Nitro-1-[3-(trifluoromethyl)phenyl]ethanaminehydrochloride

Of the compound from Example 12A, 340 mg (1.02 mmol) were admixed at RTwith 6.8 ml of a 4N solution of hydrogen chloride in dioxane, andstirred for 1 h. The reaction mixture was concentrated under reducedpressure and dried in an HV. This gave 274 mg (99% of theory) of thetitle compound.

LC/MS [Method 4]: R_(t)=0.54 min; m/z=235 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.98 (br.s, 3H), 8.05 (s, 1H), 7.92 (d,1H), 7.83 (d, 1H), 7.72 (t, 1H), 5.17-5.36 (m, 3H).

Example 14A tert-Butyl{(phenylsulphonyl)[2-(trifluoromethyl)phenyl]methyl}carbamate

In the same way as for Example 10A, the title compound (4.09 g, 34% oftheory) was obtained from 5.00 g (28.7 mmol) of2-(trifluoromethyl)benzenecarbaldehyde.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.88 (d, 1H), 8.20 (d, 1H), 7.79-7.88 (m,5H), 7.68 (q, 3H), 6.32 (d, 1H), 1.19 (s, 9H).

Example 15A tert-Butyl{(E)-[2-(trifluoromethyl)phenyl]methylidene}carbamate

In the same way as for Example 11A, the title compound −2.61 g (97% oftheory)—was obtained from 4.09 g (9.85 mmol) of the compound fromExample 14A.

MS [DCI]: m/z=274 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=9.02 (br.s, 1H), 8.25 (br.s, 1H), 7.90-7.97(m, 1H), 7.85 (dd, 2H), 1.52 (s, 9H).

Example 16A tert-Butyl{2-nitro-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate

In the same way as for Example 12A, the title compound −1.54 g (84% oftheory)—was obtained from 1.50 g (5.49 mmol) of the compound fromExample 15A.

LC/MS [Method 5]: R_(t)=1.13 min; ES⁻: m/z=333 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=8.04 (d, 1H), 7.80 (d, 1H), 7.70-7.77 (m,2H), 7.55 (t, 1H), 5.72 (t, 1H), 4.77 (dd, 1H), 4.62-4.71 (m, 1H), 1.33(s, 9H).

Example 17A 2-Nitro-1-[2-(trifluoromethyl)phenyl]ethanaminehydrochloride

In the same way as for Example 13A, from 770 mg (2.30 mmol) of thecompound from Example 16A, the title compound was obtained: 656 mg(quant., slightly contaminated).

LC/MS [Method 2]: R_(t)=0.99 min; m/z=235 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=9.22 (br.s, 3H), 8.11 (d, 1H), 7.83-7.91(m, 2H), 7.70 (t, 1H), 5.32-5.41 (m, 1H), 5.14-5.21 (m, 2H).

Example 18A tert-Butyl[(2,3-dichlorophenyl)(phenylsulphonyl)methyl]carbamate

In the same way as for Example 10A, from 5.00 g (28.6 mmol) of2,3-dichlorobenzenecarbaldehyde, the title compound was obtained: 2.22 g(19% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ=8.93 (d, 1H), 7.96 (d, 1H), 7.84 (d, 2H),7.76 (d, 2H), 7.63-7.71 (m, 2H), 7.51 (t, 1H), 6.60 (d, 1H), 1.21 (s,9H).

Example 19A tert-Butyl [(E)-(2,3-dichlorophenyl)methylidene]carbamate

In the same way as for Example 11A, from 2.22 g (5.33 mmol) of thecompound from Example 18A, the title compound was obtained: 1.38 g (94%of theory).

MS [DCI]: m/z=274 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=9.11 (s, 1H), 8.01 (d, 1H), 7.92 (d, 1H),7.52 (t, 1H), 1.52 (s, 9H).

Example 20A tert-Butyl{2-nitro-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate

In the same way as for Example 12A, from 1.38 g (5.03 mmol) of thecompound from Example 19A, the title compound was obtained: 865 mg (51%of theory).

LC/MS [Method 5]: R_(t)=1.17 min; m/z=333 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=8.07 (d, 1H), 7.64 (d, 1H), 7.50 (d, 1H),7.44 (t, 1H), 5.74 (t, 1H), 4.87 (d, 1H), 4.62 (t, 1H), 1.34 (s, 9H).

Example 21A 1-(2,3-Dichlorophenyl)-2-nitroethanamine hydrochloride

In the same way as for Example 13A, from 430 mg (1.28 mmol) of thecompound from Example 20A, the title compound was obtained: 363 mg(quant., 90% purity).

LC/MS [Method 6]: R_(t)=0.54/0.61 min; m/z=234 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=9.03 (br.s, 3H), 7.81 (d, 1H), 7.78 (dd,1H), 7.54 (t, 1H), 5.45 (dd, 1H), 5.22-5.28 (m, 2H).

Example 22A tert-Butyl{2-amino-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate

Of the compound from Example 12A, 248 mg (1.04 mmol) were introduced inmethanol and admixed with 20 mg of palladium (10% on activated carbon).Hydrogenation took place under atmospheric pressure at RT overnight. Thereaction mixture was filtered and the filtrate concentrated underreduced pressure. This gave 300 mg (88% of theory) of the titlecompound.

LC/MS [Method 5]: R_(t)=0.74 min; m/z=305 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆) (principal rotamer): δ=7.51-7.72 (m, 4H), 7.44(d, 1H), 4.50 (d, 1H), 2.63-2.77 (m, 2H), 1.63 (br. s, 2H), 1.36 (s,9H).

Example 23A tert-Butyl{2-(formylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate

Of the compound from Example 22A, 75 mg (0.25 mmol) were introduced in1.5 ml of THF and admixed at 0° C. in small portions with 43.25 mg (0.26mmol) of 4-nitrophenyl formate. The mixture was stirred at 0° C. for 2 hand then at RT overnight. The solvent was removed on a rotary evaporatorand the residue was taken up in DMSO and purified by preparative HPLC(method 10). This gave 66 mg (81% of theory) of the title compound.

LC/MS [Method 2]: R_(t)=2.01 min; m/z=333 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.08 (br.s, 1H), 7.97 (s, 1H), 7.51-7.66(m, 5H), 4.71 (d, 1H), 3.40 (dt, 1H), 3.22-3.29 (m, 1H), 1.36 (s, 9H).

Example 24A N-{2-Amino-2-[3-(trifluoromethyl)phenyl]ethyl}formamidehydrochloride

Of the compound from Example 23A, 66 mg (0.2 mmol) were introduced in1.5 ml of dichloromethane and admixed at RT with 1.56 ml of a 4Nsolution of hydrogen chloride in dioxane. The reaction mixture wasstirred at RT for 1 h. The reaction mixture was freed from the volatilecomponents on a rotary evaporator and dried in an HV. This gave 50 mg(94% of theory) of the title compound.

LC/MS [Method 2]: R_(t)=0.90 min; m/z=233 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.56 (br.s, 3H), 8.19 (br.s, 1H), 8.01 (s,1H), 7.91 (s, 1H), 7.76-7.81 (m, 2H), 7.70 (d, 1H), 4.51 (t, 1H),3.50-3.71 (m, 2H).

Example 25A tert-Butyl{2-(acetylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate

Of the compound from Example 22A, 75 mg (0.25 mmol) were introduced in2.5 ml of dichloromethane together with 60 μl (0.35 mmol) ofN,N-diisopropylethylamine and admixed at RT with 21 μl (0.30 mmol) ofacetyl chloride. The mixture was stirred at RT for 1 h. The reactionmixture was diluted with ethyl acetate and washed in succession twiceeach with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, and then with saturated aqueous sodium chloridesolution, dried over sodium sulphate and freed from the solvent on arotary evaporator. Further drying in an HV gave 88 mg of the titlecompound (100% of theory).

LC/MS [Method 4]: R_(t)=0.98 min; m/z=347 (M+H)⁺

Example 26A N-{2-Amino-2-[3-(trifluoromethyl)phenyl]ethyl}acetamidehydrochloride

In the same way as for Example 13A, 70 mg (72% of theory) of the titlecompound were obtained from Example 25A.

LC/MS [Method 5]: R_(t)=0.46 min; m/z=247 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.59 (br.s, 3H), 8.11 (t, 1H), 7.90 (s,1H), 7.75-7.80 (m, 2H), 7.70 (d, 1H), 4.48 (d, 1H), 3.54-3.63 (m, 1H),3.43-3.51 (m, 1H), 1.78 (s, 3H).

Example 27A tert-Butyl{2-[(ethylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate(racemate)

A solution of the compound from Example 22A (100 mg, 0.33 mmol) in 2 mlof pyridine was admixed at RT with 62 μl of ethanesulphonyl chloride(0.66 mmol) and the resulting mixture was stirred for 1 h. Then afurther 16 μl (0.17 mmol) of ethanesulphonyl chloride were added. Themixture was stirred for 1 h more, diluted with ethyl acetate andextracted by shaking in succession twice each with 1M hydrochloric acid,saturated aqueous sodium hydrogen carbonate solution and saturatedaqueous sodium chloride solution. The organic phase was dried oversodium sulphate and concentrated on a rotary evaporator and the residuewas dried in an HV. This gave 114 mg (88% of theory) of the titlecompound.

LC/MS [Method 3]: R_(t)=1.24 min; m/z=297 (M+H-BOC)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=7.69 (br.s, 1H), 7.55-7.66 (m, 3H), 7.49(br.d, 1H), 7.16 (br. t, 1H), 4.67-4.75 (m, 1H), 3.12-3.38 (m, 2H),2.81-2.99 (m, 2H), 1.38 (s, 9H), 1.10 (t, 3H).

The title compound was resolved into its two enantiomers—see Examples28A and 29A—by chromatography on chiral phase (Method 15a).

Example 28A tert-Butyl{2-[(ethylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate(enantiomer I)

First-eluting enantiomer from the chromatographic enantiomer resolutionof Example 27A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=1.35 min.

Example 29A tert-Butyl {2-[(ethylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate(enantiomer II)

Last-eluting enantiomer from the chromatographic enantiomer resolutionof Example 27A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=4.02 min.

Example 30A tert-Butyl {2-[(methylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate (racemate)

A solution of the compound from Example 22A (100 mg, 0.33 mmol) in 2 mlof pyridine was admixed at RT with 66 μl (0.66 mmol) of methanesulphonylchloride and stirred for 1 h. The mixture was diluted with ethyl acetateand extracted by shaking in succession twice each with 1M hydrochloricacid, saturated aqueous sodium hydrogen carbonate solution and saturatedaqueous sodium chloride solution. The organic phase was dried oversodium sulphate and concentrated on a rotary evaporator and the residuewas dried in an HV. This gave 121 mg (96% of theory) of the titlecompound.

LC/MS [Method 5]: R_(t)=1.04 min; ESI pos.: m/z=297 (M+H-BOC)⁺, ESIneg.: m/z=381 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ=7.68 (br.s, 1H), 7.55-7.66 (m, 3H), 7.50(br.d, 1H), 7.15 (br. t, 1H), 4.67-4.75 (m, 1H), 3.13-3.27 (m, 2H), 2.80(s, 3H), 1.36 (s, 9H).

The title compound was resolved into its two enantiomers—see Examples31A and 32A—by chromatography on chiral phase (Method 15a).

Example 31A text-Butyl{2-[(methylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate(enantiomer I)

First-eluting enantiomer from the chromatographic enantiomer resolutionof Example 30A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=1.74 min.

Example 32A tert-Butyl{2-[(methylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate(enantiomer II)

Last-eluting enantiomer from the chromatographic enantiomer resolutionof Example 30A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=3.47 min.

Example 33A tert-Butyl{2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate

In a continuous-flow hydrogenation apparatus (H-Cube from Thales Nano,Budapest, Model HC-2-SS) a solution of 770 mg (2.30 mmol) of thecompound from Example 16A in 135 ml of methanol was hydrogenated(conditions: Raney nickel cartridge, flow rate of 1 ml/min, 45° C.,standard hydrogen pressure). The resulting solution was concentrated ona rotary evaporator and the residue was dried briefly in an HV. Thisgave 669 mg (95% of theory) of the title compound.

LC/MS [Method 2]: R_(t)=1.39 min; m/z=305(M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆) (principal rotamer): δ=7.57-7.68 (m, 3H), 7.51(br.d, 1H), 7.43 (t, 1H), 4.77 (br.s, 1H), 2.66 (dd, 1H), 2.58 (m, 1H),1.51 (br. s, 2H), 1.35 (s, 9H).

Example 34A tert-Butyl{2-[(ethylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate(racemate)

A solution of the compound from Example 33A (100 mg, 0.33 mmol) in 2 mlof pyridine was admixed at RT with 62 μl of ethanesulphonyl chloride(0.66 mmol) and the resulting mixture was stirred for 1 h. Then afurther 16 μl (0.66 mmol) of ethanesulphonyl chloride were added. Themixture was stirred for 1 h more, diluted with ethyl acetate andextracted by shaking in succession twice each with 1M hydrochloric acid,saturated aqueous sodium hydrogen carbonate solution and saturatedaqueous sodium chloride solution. The organic phase was dried oversodium sulphate and concentrated on a rotary evaporator and the residuewas dried in an HV. This gave 113 mg (87% of theory) of the titlecompound.

LC/MS [Method 3]: R_(t)=1.24 min; m/z=297 (M+H-BOC)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=7.75 (d, 1H), 7.65-7.71 (m, 2H), 7.44-7.50(m, 2H), 7.31 (br. t, 1H), 4.95-5.05 (m, 1H), 3.03-3.18 (m, 2H),2.84-3.03 (m, 2H), 1.35 (s, 9H), 1.12 (t, 3H).

The title compound was resolved into its two enantiomers—see Examples35A and 36A—by chromatography on chiral phase (Method 15a).

Example 35A tert-Butyl{2-[(ethylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate(enantiomer I)

First-eluting enantiomer from the chromatographic enantiomer resolutionof Example 34A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=1.65 min.

Example 36A tert-Butyl {2-[(ethylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate(enantiomer II)

Last-eluting enantiomer from the chromatographic enantiomer resolutionof Example 34A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=2.86 min.

Example 37A tert-Butyl{2-[(methylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate(racemate)

In the same way as for the preparation of Example 30A, from the compoundof Example 33A (100 mg, 0.33 mmol), 119 mg (95% of theory) of the titlecompound were obtained.

LC/MS [Method 5]: R_(t)=1.01 min; ESI pos: m/z=283 (M+H-BOC)⁺, ESI neg:m/z=381 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=7.73 (d., 1H), 7.65-7.73 (m, 2H), 7.44-7.53(m, 2H), 7.27 (br. t, 1H), 4.98-5.08 (m, 1H), 3.04-3.18 (m, 2H), 2.84(s, 3H), 1.35 (s, 9H).

The title compound was resolved into its two enantiomers—see Examples38A and 39A—by chromatography on chiral phase (Method 15a).

Example 38A tert-Butyl{2-[(methylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate(enantiomer I)

First-eluting enantiomer from the chromatographic enantiomer resolutionof Example 37A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=2.04 min.

Example 39A tert-Butyl{2-[(methylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate(enantiomer II)

Last-eluting enantiomer from the chromatographic enantiomer resolutionof Example 37A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=7.41 min.

Example 40A tert-Butyl [2-amino-1-(2,3-dichlorophenyl)ethyl]carbamate

In a continuous-flow hydrogenation apparatus (H-Cube from Thales Nano,Budapest, Model HC-2-SS) a solution of 440 mg (1.31 mmol) of thecompound from Example 20A in 100 ml of methanol was hydrogenated(conditions: Raney nickel cartridge, flow rate of 1 ml/min, 40° C.,standard hydrogen pressure). The resulting solution was concentrated ona rotary evaporator and the residue was briefly dried in an HV. Thisgave 370 mg (91% of theory) of the title compound.

LC/MS [Method 5]: R_(t)=0.76 min; m/z=305 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=7.55 (br.d, 1H) 7.51 (dd, 1H), 7.31-7.39(m, 2H), 4.81-4.89 (m, 1H), 2.72 (dd, 1H), 2.59 (d, 1H), 1.66 (br. s,2H), 1.36 (s, 9H).

Example 41A tert-Butyl{1-(2,3-dichlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}carbamate(racemate)

Using the same process as for Example 27A, from 100 mg of the compoundfrom Example 40A (0.33 mmol), 101 mg (78% of theory) of the titlecompound were obtained.

LC/MS [Method 3]: R_(t)=1.21 min; ESI pos: m/z=297 (M+H-BOC)⁺; ESI neg:m/z=395 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=7.56 (dd, 1H), 7.52 (br.d, 1H), 7.46 (dd,1H), 7.39 (t, 1H), 7.29 (br. t, 1H), 5.02-5.11 (m, 1H), 3.04-3.22 (m,2H), 2.86-3.02 (m, 2H), 1.36 (s, 9H), 1.14 (t, 3H).

The title compound was resolved into its two enantiomers—see Examples42A and 43A—by chromatography on chiral phase (Method 15a).

Example 42A tert-Butyl{1-(2,3-dichlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}carbamate(enantiomer I)

First-eluting enantiomer from the chromatographic enantiomer resolutionof Example 41A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=1.94 min.

Example 43A tert-Butyl{1-(2,3-dichlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}carbamate(enantiomer II)

Last-eluting enantiomer from the chromatographic enantiomer resolutionof Example 41A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=3.67 min.

Example 44A tert-Butyl{1-(2,3-dichlorophenyl)-2-[(methylsulphonyl)amino]ethyl}carbamate(racemate)

In the same way as for the preparation of Example 30A, from the compoundof Example 40A (100 mg, 0.33 mmol), 113 mg (90% of theory) of the titlecompound were obtained.

LC/MS [Method 5]: R_(t)=1.05 min; ESI pos: m/z=283 (M+H-BOC)⁺, ESI neg:m/z=381 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=7.56 (dd, 1H), 7.53 (br.d, 1H), 7.47 (dd,1H), 7.39 (t, 1H), 7.24 (t, 1H), 5.05-5.15 (m, 1H), 3.05-3.23 (m, 2H),2.85 (s, 3H), 1.38 (s, 9H).

The title compound was resolved into its two enantiomers—see Examples45A and 46A—by chromatography on chiral phase (Method 15a).

Example 45A tert-Butyl{1-(2,3-dichlorophenyl)-2-[(methylsulphonyl)amino]ethyl}carbamate(enantiomer I)

First-eluting enantiomer from the chromatographic enantiomer resolutionof Example 44A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=1.88 min.

Example 46A tert-Butyl{1-(2,3-dichlorophenyl)-2-[(methylsulphonyl)amino]ethyl}carbamate(enantiomer II)

Last-eluting enantiomer from the chromatographic enantiomer resolutionof Example 44A by Method 15a.

Chiral analytical HPLC [Method 16]: R_(t)=10.30 min.

Example 47AN-{2-Amino-2-[3-(trifluoromethyl)phenyl]ethyl}methanesulphonamidehydrochloride (enantiomer II)

A solution of 57 mg (0.15 mmol) of the compound from Example 32A in 2 mlof dichloromethane was admixed with 2 ml of a 4N solution of hydrogenchloride in dioxane, and left with stirring at RT for 2 h. The volatilecomponents were removed on a rotary evaporator. The residue was admixedwith 5 ml of dichloromethane, the components were stirred together, andthe mixture was concentrated again on a rotary evaporator and dried inan HV. This gave 52 mg (quant.) of the title compound in 85% purity.

LC/MS [Method 3]: R_(t)=0.55 min; ESI pos.: m/z=283 (M+H)⁺

The same process was used to prepare Examples 48A to 58A:

Example Reactant Analysis No. Name Structure Ex. No. LC-MS 48AN-{2-Amino-2-[3- (trifluoromethyl)phenyl]- ethyl}ethanesulphon- amidehydrochloride (Enantiomer I)

28A [Method 4] R_(t) = 0.55 min; m/z = 297 (M + H)⁺ 49A N-{2-Amino-2-[3-(trifluoromethyl)phenyl]- ethyl}ethanesulphon- amide hydrochloride(Enantiomer II)

29A [Method 4] R_(t) = 0.56 min; m/z = 297 (M + H)⁺ 50A N-{2-Amino-2-[3-(trifluoromethyl)phenyl]- ethyl}methanesulphon- amide hydrochloride(Enantiomer I)

31A [Method 4] R_(t) = 0.46 min; m/z = 283 (M + H)⁺ 51A N-{2-Amino-2-[2-(trifluoromethyl)phenyl]- ethyl}ethanesulphon- amide hydrochloride(Enantiomer I)

35A [Method 4] R_(t) = 0.50 min; m/z = 297 (M + H)⁺ 52A N-{2-Amino-2-[2-(trifluoromethyl)phenyl]- ethyl}ethanesulphon- amide hydrochloride(Enantiomer II)

36A [Method 4] R_(t) = 0.49 min; m/z = 297 (M + H)⁺ 53A N-{2-Amino-2-[2-(trifluoromethyl)phenyl]- ethyl}methanesulphon- amide hydrochloride(Enantiomer I)

38A [Method 4] R_(t) = 0.40 min; m/z = 283 (M + H)⁺ 54A N-{2-Amino-2-[2-(trifluoromethyl)phenyl]- ethyl}methanesulphon- amide hydrochloride(Enantiomer II)

39A [Method 4] R_(t) = 0.38 min; m/z = 283 (M + H)⁺ 55AN-{2-Amino-2-(2,3- dichlorophenyl)ethyl}- ethanesulphonamidehydrochloride (Enantiomer I)

42A [Method 4] R_(t) = 0.54 min; m/z = 297 (M + H)⁺ 56AN-{2-Amino-2-(2,3- dichlorophenyl)ethyl}- ethanesulphonamidehydrochloride (Enantiomer II)

43A [Method 4] R_(t) = 0.55 min; m/z = 297 (M + H)⁺ 57AN-{2-Amino-2-(2,3- dichlorophenyl)ethyl}- methanesulphonamidehydrochloride (Enantiomer I)

45A [Method 4] R_(t) = 0.45 min; m/z = 283 (M + H)⁺ 58AN-{2-Amino-2-(2,3- dichlorophenyl)ethyl}- methanesulphonamidehydrochloride (Enantiomer II)

46A [Method 4] R_(t) = 0.44 min; m/z = 297 (M + H)⁺

Example 59A tert-Butyl{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate

A solution of 4.00 g (12.5 mmol) ofN-tert-butoxycarbonyl-2-(3-trifluoromethylphenyl)-DL-glycine and 2.1 ml(15 mmol) of triethylamine in 50 ml of THF was cooled at 0° C. andadmixed dropwise with 1.79 ml (13.8 mmol) of isobutyl chloroformate. Theresulting thick suspension was stirred at 0° C. for 1 h more, thenfiltered into a cooled flask. The solid was washed with a little THF andthe entire filtrate was added slowly dropwise to an ice-cooledsuspension of sodium borohydride (1.42 g, 37.6 mmol) in 6 ml of water(strong gas evolution). The mixture was stirred vigorously at 0° C. for1 h more, then admixed with 5 ml of 1N hydrochloric acid and extractedthree times with ethyl acetate. The organic phase was washed with 1Naqueous sodium hydroxide solution and then twice with saturated aqueoussodium hydrogen carbonate solution, dried over sodium sulphate andconcentrated on a rotary evaporator. The residue was purified bypreparative HPLC (Method 10). This gave 2.00 g of the title compound(52% of theory).

LC/MS [Method 5]: R_(t)=1.02 min; m/z=328 (M+Na)⁺, 206 (M+H-BOC)⁺.

¹H NMR (DMSO-d₆, 00 MHz): δ=7.65 (s, 1H), 7.51-7.62 (m, 3H), 7.37 (br.d, 1H), 4.86 (t, 1H), 4.57-4.66 (m, 1H), 3.46-3.58 (m, 2H), 1.37 (s,9H).

Example 60A 2-Amino-2-[3-(trifluoromethyl)phenyl]ethyl carbamatehydrochloride

A solution of 1.00 g (3.28 mmol) of a compound from Example 59A in 20 mlof acetonitrile was cooled to −15° C. and admixed with 399 μl (4.59mmol) of chlorosulphonyl isocyanate. After 10 min, 18 ml of water wereadded and the mixture was heated at 60° C. for 2 h. After cooling to RT,the solution was rendered alkaline (pH 9-10) by addition of saturatedaqueous sodium hydrogen carbonate solution and extracted three timeswith ethyl acetate. The combined organic phases were dried over sodiumsulphate and freed from the solvents on a rotary evaporator. Forcomplete deprotection of the amino group, the residue was admixed with15 ml of a 4M solution of hydrogen chloride in dioxane, and this mixturewas stirred at RT for 5 min and concentrated on a rotary evaporator.Drying of the residue in an HV gave 785 mg (84% of theory) of the titlecompound.

LC/MS [Method 4]: R_(t)=0.44 min; m/z=249 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.80 (br.s, 3H), 7.97 (s, 1H), 7.88 (d,1H), 7.80 (d, 1H), 7.70 (t, 1H), 6.61 (br. s, 2H), 4.63-4.73 (m, 1H),4.26-4.38 (m, 2H).

Example 61A 2-Amino-2-[2-(trifluoromethyl)phenyl]ethanol hydrochloride

A quantity of 500 mg (2.28 mmol) of (2-trifluoromethylphenyl)-DL-glycinewas added in portions under argon to a 1M borane-THF complex solution inTHF (9.13 ml, 9.13 mmol) which was cooled with ice water. After 10 min,the cooling bath was removed and the mixture was stirred at RT for 4 h.For work-up, the pH was made acidic by addition of 1N hydrochloric acid,the THF was removed on a rotary evaporator, and the aqueous solutionremaining was neutralized with 1N aqueous sodium hydroxide solution andthen rendered alkaline with saturated aqueous sodium hydrogen carbonatesolution. It was extracted three times with ethyl acetate. The combinedorganic phases were dried over sodium sulphate and freed from thesolvent on a rotary evaporator. The resulting crude amino alcohol wasadmixed with 15 ml of a 4M solution of hydrogen chloride in dioxane, andstirred for 5 minutes. The solution was then concentrated on a rotaryevaporator. Drying of the residue in an HV gave the title compound (550mg, quant.) which was reacted further without purification.

LC/MS [Method 2]: R_(t)=0.78 min; m/z=206 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.71 (br.s, 3H), 7.92 (d, 1H), 7.78-7.86(m, 2H), 7.64 (t, 1H), 5.75 (t, 1H), 4.42 (dd, 1H), 3.64-3.77 (m, 2H).

Example 62A tert-Butyl{2-hydroxy-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate

Of the compound from Example 61A, 367 mg (1.52 mmol) were dissolved in20 ml of dioxane and 20 ml of 5% strength aqueous sodium hydrogencarbonate solution, the solution was admixed with 356 μl (1.55 mmol) ofdi-tert-butyl dicarbonate, and the mixture was stirred at RT overnight.It was extracted five times with ethyl acetate. The combined organicphases were dried over sodium sulphate and concentrated on a rotaryevaporator. The residue corresponded to the title compound (338 mg, 73%of theory).

LC/MS [Method 2]: R_(t)=2.01 min; m/z=306 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz) (rotamers): δ=7.61-7.71 (m, 3H), 7.37-7.48 (m,2H), 4.90-5.01 (m, 2H), 3.35-3.50 (m, 2H), 1.35 (br.s about 7.5H)⁺1.10(br.s, 1.5H).

Example 63A 2-Amino-2-[2-(trifluoromethyl)phenyl]ethyl carbamatehydrochloride

A solution of 570 mg (1.87 mmol) of the compound from Example 62A in 100ml of acetonitrile was cooled to −15° C. and admixed with 325 μl (3.73mmol) of chlorosulphonyl isocyanate. After 10 min, 50 ml of water wereadded and the mixture was heated at 60° C. for 4 h. After cooling to RT,the solution was rendered alkaline (pH 9-10) by addition of saturatedaqueous sodium hydrogen carbonate solution and extracted three timeswith ethyl acetate. The combined organic phases were dried over sodiumsulphate and freed from the solvents on a rotary evaporator. Forcomplete deprotection of the amino group, the residue was admixed with15 ml of a 4M solution of hydrogen chloride in dioxane, and the mixturewas stirred at RT for 5 min and the volatile components were removed ona rotary evaporator. The residue corresponded to the title compound (630mg, quant.).

LC/MS [Method 4]: R_(t)=0.34 min; m/z=249 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.97 (br.s, 3H), 8.06 (d, 1H), 7.80-7.87(m, 2H), 7.66 (t, 1H), 6.64 (br.s, 2H), 4.64 (br.s, 1H), 4.37 (dd, 1H),4.27 (dd, 1H).

Example 64A tert-Butyl [(1R)-1-(3-chlorophenyl)-2-hydroxyethyl]carbamate

In the same way as for Example 62A, from 134 mg (0.644 mmol) of(2R)-2-amino-2-(3-chlorophenyl)ethan-1-ol, 166 mg (95% of theory) of thetitle compound were obtained.

LC/MS [Method 1]: R_(t)=1.10 min; m/z=272 (M+H-BOC)⁺

Example 65A 2-Amino-2-(3-chlorophenyl)ethyl carbamate hydrochloride

In the same way as for Example 60A, from 166 mg (0.61 mmol) of thecompound from Example 64A, 200 mg of the title compound were obtainedand were used further as a crude product.

LC/MS [Method 4]: R_(t)=0.30 min; m/z=215 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.71 (br.s, 3H), 7.66 (s, 1H), 7.46-7.54(m, 3H), 6.62 (br. s, 2H), 4.52-4.62 (m, 1H), 4.22-4.32 (m, 2H).

Example 66A 2-Amino-2-(2-chlorophenyl)ethanol

A quantity of 4.00 g (21.6 mmol) of (2-chlorophenyl)-DL-glycine wasadded in portions under argon to a 1M boran-THF complex solution in THF(64.7 ml, 64.7 mmol) which was cooled with ice water. After 10 min, thecooling bath was removed and the mixture was stirred at RT for 4 h. Forwork-up, pieces of ice were added slowly until the evolution of gas cameto an end. The mixture was rendered alkaline by addition of 1N aqueoussodium hydroxide solution and extracted three times with MTBE. Thecombined organic phases were dried over sodium sulphate and concentratedon a rotary evaporator. The resulting crude title compound (3.00 g, 77%of theory) was reacted further without additional purification.

LC/MS [Method 4]: R_(t)=0.22 min; m/z=172 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=7.64 (d, 1H), 7.37 (d, 1H), 7.32 (t, 1H),7.24 (t, 1H), 4.87 (br.s, 1H), 4.26-4.32 (m, 1H), 3.53 (dd, 1H), 3.20(dd, 1H), 2.08 (br. s, 2H).

Example 67A tert-Butyl [1-(2-chlorophenyl)-2-hydroxyethyl]carbamate

Of the compound from Example 66A, 2.3 g (13.4 mmol) were stirred in 100ml of acetonitrile with 3.69 ml (16 mmol) of di-tert-butyl dicarbonateovernight. Then ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added. The phases were separated and the aqueousphase was extracted twice more with ethyl acetate. The combined organicphases were washed in succession with water (2×) and saturated aqueoussodium chloride solution, dried over sodium sulphate and concentrated ona rotary evaporator. The residue was dried in an HV. The resulting crudetitle compound (4.2 g) was reacted without further purification inExample 68A.

LC/MS [Method 6]: R_(t)=2.02 min; m/z=272 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz) (rotamers): δ=7.43 (dd, 1H), 7.39 (dd, 1H),7.36 (br.d, 1H), 7.32 (td, 1H), 7.25 (td, 1H), 4.94-5.02 (m, 1H), 4.91(t, 1H), 3.46-3.54 (m, 1H), 3.35-3.43 (m, 1H), 1.36 (br. s, 7.5H)+1.16(br. s, 1.5H).

Example 68A 2-Amino-2-(2-chlorophenyl)ethyl carbamate hydrochloride

In the same way as for Example 63A, from 2.00 g (7.36 mmol) of thecompound from Example 67A, the title compound was obtained (1.10 g, 69%of theory over 2 stages).

LC/MS [Method 4]: R_(t)=0.28 min; m/z=215 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.76 (br.s, 3H), 7.75 (d, 1H), 7.57 (dd,1H), 7.41-7.53 (m, 2H), 6.64 (br.s, 2H), 4.82-4.92 (m, 1H), 4.27 (qd[ABX], 2H).

Example 69A (2R)-2-Amino-2-[3-(trifluoromethyl)phenyl]propan-1-olhydrochloride

A 1M solution of the borane-tetrahydrofuran complex in THF (37.1 ml,37.1 mmol) was cooled to 0° C. under argon. Added thereto were 2.5 g(9.27 mmol) of (2R)-2-amino-2-[3-(trifluoromethyl)phenyl]propanoic acid,and, following removal of the cooling bath, the mixture was stirred atRT for 4 h. For work-up, it was cautiously acidified with 1Nhydrochloric acid. The THF was removed on a rotary evaporator. Theaqueous phase was rendered basic with saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. Thecombined organic phases were dried over sodium sulphate and concentratedon a rotary evaporator. The resulting crude product (2.4 g) was reactedfurther without purification.

LC/MS [Method 2]: R_(t)=0.93 min; m/z=218 (M+H)⁺

Example 70A tert-Butyl{(2R)-1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate

Of the compound from Example 69A, 2.032 g (9.27 mmol) were dissolved in50 ml of dichloromethane and 10 ml of dioxane, and the solution wasadmixed with 2.17 ml (9.45 mmol) of di-tert-butyl dicarbonate. Themixture was stirred at RT overnight, then freed from the volatilecomponents on a rotary evaporator. The residue was dried in an HV andthen purified by preparative HPLC (Method 10). This gave 2.69 g (91%over theory of 2 stages) of the title compound.

LC/MS [Method 5]: R_(t)=1.09 min; m/z=342 (M+Na)⁺.

¹H NMR (DMSO-d₆, 400 MHz) (rotamers): δ=7.50-7.64 (m, 5H), 6.92 (br. s,1H), 4.97 (br. t, 1H), 3.43-3.54 (m [AB], 3H), 1.58 (s, 3H), 1.34+1.00(2 br.s, in total 9H).

Example 71A (2R)-2-Amino-2-[3-(trifluoromethyl)phenyl]propyl carbamatehydrochloride

A solution of 520 mg (1.63 mmol) of the compound from Example 70A in 10ml of acetonitrile was cooled to −15° C. and admixed with 198 μl (2.28mmol) of chlorosulphonyl isocyanate. After 10 min, 18 ml of water wereadded and the mixture was heated at 60° C. overnight. After cooling toRT, the solution was rendered alkaline by addition of saturated aqueoussodium hydrogen carbonate solution and extracted three times with ethylacetate. The combined organic phases were dried over sodium sulphate andfreed from the solvents on a rotary evaporator. For completedeprotection of the amino group, the residue was admixed with 5 ml of a4M solution of hydrogen chloride in dioxane, and this mixture wasstirred at RT for 5 min and concentrated on a rotary evaporator. Dryingof the residue in an HV gave the title compound (440 mg, 90% of theory).

LC/MS [Method 4]: R_(t)=0.47 min; m/z=263 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.80 (br.s, 3H), 7.97 (s, 1H), 7.88 (d,1H), 7.80 (d, 1H), 7.70 (t, 1H), 6.61 (br. s, 2H), 4.63-4.73 (m, 1H),4.26-4.38 (m, 2H).

Example 72A(2R)-2-[(tert-Butoxycarbonyl)amino]-2-(2-chlorophenyl)propanoic acid

A quantity of 500 mg (2.11 mmol) of(2R)-2-amino-2-[2-(chloromethyl)phenyl]propionoic acid was dissolved in10 ml of 5% strength sodium hydrogen carbonate solution and admixed with10 ml of dioxane and then with 511 μl (2.22 mmol) of di-tert-butyldicarbonate. The mixture was stirred overnight, adjusted cautiously with1N hydrochloric acid to a pH of 2, and extracted three times with ethylacetate. The combined organic phases were dried over sodium sulphate andconcentrated on a rotary evaporator. The residue (322 mg, 51% of theory)corresponded to the title compound and was reacted further as such.

LC/MS [Method 3]: R_(t)=1.08 min; m/z=322 (M+Na)⁺

Example 73A tert-Butyl[(2R)-2-(2-chlorophenyl)-1-hydroxypropan-2-yl]carbamate

In the same way as for Example 59A, from 150 mg (0.5 mmol) of thecompound from Example 72A, 110 mg of the title compound were obtained(77% of theory).

LC/MS [Method 4]: R_(t)=0.98 min; m/z=286 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=7.44 (d, 1H), 7.32 (d, 1H), 7.17-7.29 (m,2H), 6.79 (br. s, 1H), 4.96 (br. t, 1H), 3.60-3.82 (m, 2H), 1.64 (s,3H), 1.33 (s, 9H).

Example 74A (2R)-2-Amino-2-(2-chlorophenyl)propan-1-ol hydrochloride

In the same way as for Example 47A, from 55 mg (0.19 mmol) of thecompound from Example 73A, by treatment with a 4N solution of hydrogenchloride in dioxane, 49 mg (approximately 85% purity) of the titlecompound were obtained. It was reacted without purification.

LC/MS [Method 5]: R_(t)=0.28 min; m/z=186 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.63 (br.s, 3H), 7.52 (d, 1H), 7.34-7.49(m, 3H), 5.69 (br.s, 1H), 4.11 (dd, 1H), 3.83 (dd, 1H), 1.70 (s, 3H).

Example 75A (2R)-2-Amino-2-(2-chlorophenyl)propyl carbamate

A solution of 55 mg (0.19 mmol) of the compound from Example 73A in 2 mlof acetonitrile was admixed at RT in 3 portions over the course of 20min with 39 μl (0.42 mmol) of chlorosulphonyl isocyanate. After afurther 10 min, 2 ml of water were added and the mixture was heated at60° C. for 2 h. After cooling to RT, the solution was rendered alkalineby addition of 2N aqueous sodium hydrogen carbonate solution andextracted three times with ethyl acetate. The combined organic phaseswere dried over sodium sulphate and concentrated on a rotary evaporator.Drying of the residue in an HV gave the slightly contaminated titlecompound (34 mg, 77% of theory, 90% purity), which was reacted furtheras such.

¹H NMR (DMSO-d₆, 400 MHz): δ=7.76 (dd, 1H), 7.38 (dd, 1H), 7.32 (td,1H), 7.26 (td, 1H), 6.27-6.51 (br. s, 2H), 4.36 (d, 1H), 4.24 (d, 1H),2.11-2.42 (br.s, 2H), 1.48 (s, 3H).

Example 76A Methyl{3-(4-chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate

280 mg (0.74 mmol) of the compound from Example 7A were introduced at RTtogether with 108.1 mg (0.89 mmol) of 4-dimethylaminopyridine in 5.3 mlof pyridine, admixed with portions of 0.31 ml (1.84 mmol) oftrifluoromethanesulphonic anhydride and stirred for 12 h. The pyridinewas removed on a rotary evaporator and the residue was taken up inacetonitrile and 1N hydrochloric acid. The product was purified bypreparative HPLC (Method 10). This gave 230 mg (86% of theory) of thetitle compound.

LC/MS [Method 4]: R_(t)=1.14 min; m/z=362 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=7.68 (s, 4H), 7.18 (d, 1H), 6.85 (dd, 1H),4.78 (s, 2H), 3.72 (s, 3H).

Example 77A{3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}aceticacid

Of the compound from Example 76A, 260 mg (0.72 mmol) were dissolved in 5ml of methanol and admixed with 2.87 ml (2.87 mmol) of a 1M solution oflithium hydroxide in water. The mixture was stirred at RT for 1 h, thenacidified with 1N hydrochloric acid and diluted with DMSO. The entiresolution was purified by preparative HPLC (Method 10). This gave 215 mg(86% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.03 min; m/z=348 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.31 (br. s, 1H), 7.68 (s, 4H), 7.19 (dd,1H), 6.79-6.92 (m, 1H), 4.64 (s, 2H).

Example 78A 3-Amino-3-[3-(trifluoromethyl)phenyl]propan-1-olhydrochloride

With ice cooling and under argon, 2.57 ml (2.57 mmol) of 1M borane-THFcomplex solution were introduced and were admixed with 150 mg (0.64mmol) of 3-amino-3-[3-(trifluoromethyl)phenyl]propanoic acid. After 10min, the cooling bath was removed and the mixture was stirred at RT for4 h. With ice cooling, 1 ml of 3N aqueous sodium hydroxide solution wasadded dropwise and the mixture was stirred overnight. The reactionsolution was acidified using 1N hydrochloric acid. The THF was removedon a rotary evaporator and the aqueous solution obtained was purified bypreparative HPLC (Method 10). This gave 160 mg (97% of theory) of thetitle compound.

LC/MS [Method 1]: R_(t)=1.08 min; m/z=220 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.19 (s, 1H), 7.90 (s, 1H), 7.80 (d, 1H),7.74 (d, 1H), 7.66 (t, 1H), 4.42 (dd, 1H), 3.40 (dt, 1H), 3.25 (ddd,1H), 2.04-2.16 (m, 1H), 1.87-1.97 (m, 1H).

Example 79A tert-Butyl{(1S)-3-hydroxy-1-[2-(trifluoromethyl)phenyl]propyl}carbamate

With ice cooling and under argon, 6 ml (6 mmol) of a 1M borane-THFcomplex solution were introduced and were admixed with(S)-Boc-2-(trifluoromethyl)-B-phenylalanine (500 mg, 1.50 mmol). Themixture was stirred at 0° C. for 1 h. To remove the excess borane,pieces of ice were added. At the end of the evolution of gas, saturatedaqueous sodium hydrogen carbonate solution was added and this mixturewas extracted with ethyl acetate. The aqueous phase was acidified with1N hydrochloric acid and extracted twice with ethyl acetate. Thesecombined organic phases were washed with 1N hydrochloric acid and thenwith saturated aqueous sodium chloride solution, dried over sodiumsulphate and concentrated on a rotary evaporator. The residue was driedin an HV and corresponded to the title compound (340 mg, 71% of theory).

LC/MS [Method 3]: R_(t)=1.15 min; m/z=220 (M+H-BOC)⁺

Example 80A (3S)-3-Amino-3-[2-(trifluoromethyl)phenyl]propan-1-olhydrochloride

Of the compound from Example 79A, 150 mg (0.47 mmol) were stirred for 20min in 3 ml of a 4N solution of hydrogen chloride in dioxane. Thevolatile components were removed on a rotary evaporator and the residuewas dried in an HV. This gave 140 mg (87% purity) of the title compound.

LC/MS [Method 3]: R_(t)=1.15 min; m/z=220 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.69 (br.s, 3H), 7.98 (d, 1H), 7.73-7.89(m, 2H), 7.62 (t, 1H), 4.59 (br.s, 1H), 3.61-3.81 (m, 1H), 3.40-3.48 (m,2H), 2.10-2.22 (m, 1H), 1.92-2.02 (m, 1H).

Example 81A (3S)-3-Amino-3-[2-(trifluoromethyl)phenyl]propyl carbamatehydrochloride

In the same way as for Example 63A, from 180 mg (0.70 mmol) of thecompound from Example 79A, 190 mg (90% of theory) of the title compoundwere obtained.

LC/MS [Method 2]: R_(t)=0.97 min; m/z=263 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.72 (br.s, 3H), 7.99 (d, 1H), 7.80-7.87(m, 2H), 7.65 (t, 1H), 6.50 (br.s, 2H), 4.48-4.60 (m, 1H), 3.77-3.93 (m,2H), 2.29-2.39 (m, 1H), 2.12-2.23 (m, 1H).

Example 82A3-[(tert-Butoxycarbonyl)amino]-3-(2,3-dichlorophenyl)propanoic acid

A quantity of 1.50 g (6.41 mmol) of3-amino-3-(2,3-dichlorophenyl)propanoic acid was suspended in 45 ml ofdioxane and 45 ml of 5% strength aqueous sodium hydrogen carbonatesolution and the suspension was admixed at room temperature with 1.40 g(6.41 mmol) of di-tert-butyl dicarbonate. The mixture was stirred atroom temperature for 16 h. For work-up, the suspension was admixed withabout 50 ml of ethyl acetate, with stirring. The precipitate wasfiltered off with suction. Following phase separation of the motherliquor, the aqueous phase was adjusted cautiously to a pH of 1 using 1Nhydrochloric acid and extracted once with about 50 ml of ethyl acetate.The combined organic phases were dried over sodium sulphate, filteredand concentrated under reduced pressure. This gave 1.68 g (79% oftheory) of the target compound.

LC-MS [Method 3] R_(t)=1.18 min; MS [ESIneg]: m/z=332 (M−H)⁻

The following compounds were obtained similarly:

Example No. Name Structure Analysis LC-MS 83A [(tert-Butoxycarbonyl)amino](2,3-difluoro- phenyl)acetic acid

[Method 2] R_(t) = 2.97 min; MS [ESIpos]: m/z = 288 (M + H)⁺ 84A Methyl3-[(tert-butoxy- carbonyl)amino]-3-(2- fluorophenyl)propanoate

[Method 3] R_(t) = 1.20 min; MS [ESIpos]: m/z = 320 (M + Na)⁺

Example 85A tert-Butyl [1-(2,3-dichlorophenyl)-3-hydroxypropyl]carbamate

Of the compound from Example 82A, 430 mg (1.29 mmol) were suspended in 5ml of THF and cooled to 0° C., and the suspension was admixed with 179μl (1.29 mmol) of triethylamine and also with 184 μl (1.42 mmol) ofisobutyl chloroformate and stirred at 0° C. for 1 hour. The suspensionwas then filtered through a Seitz frit into a cooled flask, and theretained solid was washed with a little THF. The filtrate was addedslowly dropwise, with ice cooling, to a solution of 146 mg (3.86 mmol)of sodium borohydride in 0.5 ml of water and stirred at 0° C. for 1 h.For work-up, the reaction mixture was admixed with about 10 ml ofsaturated aqueous sodium hydrogen carbonate solution and extracted with50 ml of ethyl acetate. The organic phases were washed once withsaturated aqueous sodium hydrogen carbonate solution and once withsaturated aqueous sodium chloride solution. They were then dried oversodium sulphate, filtered and concentrated on a rotary evaporator. Thisgave 419 mg (95% of theory) of the target compound.

LC-MS [Method 3] R_(t)=1.20 min; MS [ESIpos]: m/z=342 (M+Na)⁺

The following compound was obtained similarly:

Example Reactant No. Name Structure Ex. No. Analysis LC-MS 86Atert-Butyl [1-(2,3- difluorophenyl)-2- hydroxyethyl]carbamate

83A [Method 2] R_(t) = 1.94 min; MS [ESIpos]: m/z = 274 (M + H)⁺

Example 87A tert-Butyl [1-(2-fluorophenyl)-3-hydroxypropyl]carbamate

Of the compound from Example 84A, 580 mg (1.95 mmol) were dissolved in 5ml of 1,2-dimethoxyethane and the solution was admixed in succession atroom temperature with 110.7 mg (2.93 mmol) of sodium borohydride and16.5 mg (0.39 mmol) of lithium chloride. The mixture was then stirred at85° C. for 16 h. For work-up, it was admixed with 15 ml of saturatedaqueous sodium potassium tartrate solution and extracted three times ineach case with 10 ml of ethyl acetate. The combined organic phases weredried over magnesium sulphate, filtered and concentrated on a rotaryevaporator. The crude product was purified by chromatography on silicagel (elution: cyclohexane/ethyl acetate 1:1). This gave 383 mg (73% oftheory) of the target compound.

LC-MS [Method 4] R_(t)=0.91 min; MS [ESIpos]: m/z=270 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=1.44 (s, 9H), 1.83-2.06 (m, 2H), 3.01 (br.s,1H), 3.68 (br.s, 2H), 4.98-5.14 (m, 1H), 5.20-5.37 (m, 1H), 7.00-7.09(m, 1H), 7.09-7.16 (m, 1H), 7.22-7.34 (m, 2H).

Example 88A 3-Amino-3-(2,3-dichlorophenyl)propyl carbamate

In the same way as for Example 63A, from 612 mg of the compound fromExample 85A, 572 mg (quant.) of the title compound were obtained as acrude product.

¹H NMR (DMSO-d₆, 400 MHz): δ=8.58 (br.s, 3H), 7.72 (dd, 2H), 7.53 (t,1H), 6.53 (br.s, 2H), 4.75-4.87 (m, 1H), 3.92 (dt, 1H), 3.73-3.80 (m,1H), 2.22-2.32 (m, 1H), 2.07-2.19 (m, 1H).

Example 89A 3-Amino-3-(2-fluorophenyl)propyl carbamate hydrochloride

Starting from 380 mg of the compound from Example 87A, in the same wayas in Example 63A, 268 mg (76% of theory) of the target compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ=2.05-2.21 (m, 1H), 2.25-2.40 (m, 1H),3.62-3.75 (m, 1H), 3.81-3.93 (m, 1H), 4.50-4.66 (m, 1H), 6.53 (br.s,2H), 7.23-7.37 (m, 2H), 7.41-7.52 (m, 1H), 7.62-7.75 (m, 1H), 8.64(br.s, 3H).

Example 90A 3-Amino-3-(2,3-dichlorophenyl)propan-1-ol

Of the compound from Example 85A, 800 mg (2.50 mmol) were dissolved in20 ml of dichloromethane and admixed at 0° C. with 1.92 ml (25.0 mmol)of trifluoroacetic acid, then stirred at room temperature for 1 hour.The mixture was freed from the solvent and from the trifluoroacetic acidon a rotary evaporator. The crude product was taken up in 20 ml oftoluene and again concentrated on a rotary evaporator under reducedpressure. Purification took place by chromatography on silica gel. Byelution with ethyl acetate it was possible to separate off apolarimpurities. Elution with dichloromethane/methanol/26% strength ammoniasolution (10:1:0.1) gave 673 mg (79% of theory) of the target compound.

LC-MS [Method 3] R_(t)=0.50 min; MS [ESIpos]: m/z=220 (M+H)⁺

Example 91A 2-Amino-2-[3-(trifluoromethyl)phenyl]ethanoltrifluoroacetate

Of the compound from Example 59A, 277 mg (0.91 mmol) were dissolved in10 ml of dichloromethane and admixed at 0° C. with 0.7 ml (0.91 mmol) oftrifluoroacetic acid, then stirred at room temperature for 1 hour. Themixture was concentrated on a rotary evaporator. The crude product wastaken up in 20 ml of toluene and again concentrated on a rotaryevaporator under reduced pressure. The crude product was purified bypreparative HPLC [Method 19]. This gave 124 mg (43% of theory) of thetarget compound.

LC-MS [Method 5] R_(t)=0.40 min; MS [ESIpos]: m/z=206(M+H)^(+(free base))

¹H-NMR (400 MHz, MeOD): δ=3.82 (dd, 2H), 3.94 (dd, 1H), 4.49 (dd, 1H),7.64-7.71 (m, 1H), 7.71-7.79 (m, 2H), 7.84 (s, 1H).

Example 92A 2-Amino-2-(2,3-difluorophenyl)ethanol hydrochloride

Of the compound from Example 86A, 103 mg (0.38 mmol) were dissolved in 2ml of dichloromethane and the solution was admixed at room temperaturewith 1.73 ml of a 4M solution of hydrogen chloride in dioxane, andstirred at room temperature for 2 hours. The mixture was concentrated ona rotary evaporator and the residue was dried in an HV. This gave 79 mg(100% of theory) of the target compound.

LC-MS [Method 4] R_(t)=0.22 min; MS [ESIpos]: m/z=173(M+H)^(+(free base))

Example 93A Methyl(3RS)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-(2-fluorophenyl)propionate

Of the compound from Example 8A, 50 mg (0.14 mmol) were dissolved in 1ml of DMF, admixed with 34 mg (0.18 mmol) of EDC and with 22 mg (0.16mmol) of HOBt, and stirred at room temperature for 10 minutes. Then 35mg (0.15 mmol) of methyl 3-amino-3-(2-fluorophenyl)propionatehydrochloride and also 20 μl (0.15 mmol) of triethylamine were added andthe mixture was left with stirring at room temperature for 16 h. Forwork-up, it was admixed with 10 ml of water and extracted with twice 10ml of ethyl acetate. The combined organic phases were dried overmagnesium sulphate, filtered and concentrated on a rotary evaporator.The crude product was purified by preparative HPLC [Method 19]. Thisgave 47 mg (63% of theory) of the target compound.

LC-MS [Method 3] R_(t)=1.22 min; MS [ESIpos]: m/z=545 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=2.80-2.96 (m, 2H), 3.53 and 3.58 (2s, 3H),3.93-4.12 (m, 2H), 4.44-4.82 (m, 3H), 5.05 (t, 1H), 5.56-5.67 (m, 1H),6.98-7.24 (m, 3H), 7.27-7.37 (m, 2H), 7.47-7.64 (m, 3H), 7.70 (d, 2H).(partial resolution of the duplicated signal set of the diastereomermixture.)

Example 94A{3-(4-Chlorophenyl)-5-oxo-4-[(3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}aceticacid

Of the compound from Example 5A, 400 mg (1.05 mmol) were reacted in thesame way as for Example 8A. This gave 328 mg (85% of theory) of thetitle compound.

LC/MS [Method 6]: R_(t)=2.01 min; m/z=366 (M+H)⁺.

Example 95A Amino[3-(trifluoromethyl)phenyl]acetic acid hydrochloride

A quantity of 1.00 g (3.13 mmol) ofN-tert-butoxycarbonyl-2-(3-trifluoromethylphenyl)-DL-glycine was admixedwith 15.7 ml of a 4N solution of hydrogen chloride in dioxane andstirred at RT overnight. The volatile components were removed on arotary evaporator. The residue was dried in an HV. This gave 795 mg (99%of theory) of the title compound.

LC/MS [Method 2]: R_(t)=0.79 min; m/z=220 (M+H)⁺

Example 96A 2-(Dibenzylamino)-2-[3-(trifluoromethyl)phenyl]ethanol

A solution of 1.48 ml (12.4 mmol) of benzyl bromide in 5 ml of ethanolwas added dropwise at RT to an initial-charge solution of 795 mg of thecompound from Example 95A (3.11 mmol) and 2.15 g (15.5 mmol) ofpotassium carbonate in 20 ml of ethanol and 5 ml of water. The resultingmixture was heated at reflux overnight. After cooling to RT, the solventwas removed on a rotary evaporator. The residue was admixed with 250 mlof water and extracted three times with ethyl acetate. The combinedorganic phases were washed twice with saturated aqueous sodium chloridesolution, dried over sodium sulphate and concentrated on a rotaryevaporator. The residue (1.72 g) contains, according to LC-MS (Method2), a mixture of N,N-dibenzylamino acid (R_(t)=2.66 min),N,N-dibenzylamino acid ethyl ester (Rt=3.21 min) and N,N-dibenzylaminoacid benzyl ester (Rt=3.32 min).

This mixture was dissolved in 50 ml of diethyl ether and added underargon to a 1M solution of lithium aluminium hydride in THF (12.9 ml,12.9 mmol) which was cooled with ice water. Then the ice bath wasremoved and the reaction mixture was heated at reflux for 1 h. Aftercooling to RT, the excess hydride was decomposed with a few drops ofwater. The mixture was stirred with sodium sulphate for a few minutesand filtered. The filtrate was concentrated on a rotary evaporator.Drying of the residue in an HV gave the title compound (730 mg, 28% oftheory).

LC/MS [Method 2]: R_(t)=2.72 min; m/z=386 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=7.59-7.70 (m, 4H), 7.29-7.38 (m, 8H),7.20-7.26 (m, 2H), 4.69 (t, 1H), 3.94-4.05 (m, 2H), 3.72-3.82 (m, 3H),3.30 (d, 1H) (possibly 1H under the water signal at 3.32 ppm).

Example 97A 2-(Dibenzylamino)-2-[3-(trifluoromethyl)phenyl]acetaldehyde

A 2M solution of oxalyl dichloride in dichloromethane was diluted underargon with 10 ml of dichloromethane and cooled to −78° C. A solution of221 μl (3.11 mmol) of DMSO in 2 ml of dichloromethane was added dropwisethereto. After 10 min, a solution of 600 mg (1.56 mmol) of the compoundfrom Example 96A in 10 ml of dichloromethane was added dropwise. Themixture was stirred at −78° C. for 15 min, then admixed with 868 μl(6.22 mmol) of triethylamine. After a further 10 min, the cooling bathwas removed and the mixture was allowed to warm to RT, then admixed with20 ml of water and 200 ml of dichloromethane. The aqueous phase wasremoved, for purification. The organic phase was washed twice with waterand then with 5% strength aqueous sodium hydrogen carbonate solution,dried over sodium sulphate and concentrated on a rotary evaporator. Theresidue was dried in an HV. The title compound (600 mg, quant.) wasreacted immediately further as the crude product.

LC/MS [Method 6]: R_(t)=3.18 min; m/z=384 (M+H)⁺

Example 98A3-(Dibenzylamino)-1,1,1-trifluoro-3-[3-(trifluoromethyl)phenyl]propan-2-ol

Of the compound from Example 97A, 300 mg (0.78 mmol) were dissolved in 5ml of THF, cooled to 0° C., and admixed with 183 μl (1.17 mmol) of(trifluoromethyl)trimethylsilane and then with 39 μl (39 μmol) of a 1Msolution of tetra-n-butylammonium fluoride in THF. The cooling bath wasremoved and the mixture was stirred at RT overnight. Following additionof 2 ml of 1N hydrochloric acid, it was stirred for a further 30 min.The THF was removed on a rotary evaporator and the product was purifiedby preparative chromatography (Method 10). This gave 168 mg (47% oftheory) of the title compound as a diastereomer mixture (ratio about3:2)

LC/MS [Method 4]: R_(t)=1.43 min+1.45 min (ratio 3:2); in each casem/z=454 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=7.52-7.77 (m, 4H), 7.38-7.41 (m, 8H),7.22-7.30 (m, 2H), 6.33 (d, 0.4H Diast.1), 6.22 (d, 0.6H Diast.2),4.97-5.09 (m, 0.6H Diast.2), 4.88-4.99 (0.4H, Diast. 1), 4.03 (d, 0.8H,Diast.1), 3.97 (d, 1.2H, Diast.2), 3.94 (d, 0.6H, Diast.2), 3.91 (d,0.4H, Diast.1), 3.03 (d, 0.8H, Diast.1), 3.87 (d, 1.2H, Diast.2).

Example 99A3-Amino-1,1,1-trifluoro-3-[3-(trifluoromethyl)phenyl]propan-2-ol

In a continuous-flow hydrogenation apparatus (H-Cube from Thales Nano,Budapest, Model HC-2-SS), a solution of 168 mg (0.37 mmol) of thecompound from Example 98A in 50 ml of methanol was hydrogenated(conditions: Pd(OH)₂/C cartridge, flow rate of 1 ml/min, RT, standardhydrogen pressure). The reaction mixture was concentrated on a rotaryevaporator and the residue was briefly dried in an HV. This was thetitle compound (93 mg, 92% of theory).

LC/MS [Method 4]: R_(t)=0.63 min+0.65 min (ratio 2:3); each m/z=274(M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=7.79 (s, 0.4H Diast.1), 7.76 (s, 0.6HDiast.2), 7.72 (d, 0.4H Diast.1), 7.67 (d, 0.6H Diast.2), 7.50-7.64 (m,2H), 6.40 (br. d, 1H), 4.03-4.21 (m, 2H).

Example 100A tert-Butyl{2-nitro-1-[3-(trifluoromethyl)phenyl]ethyl}-carbamate (non-racemicenantiomer mixture)

Under argon, 9.75 ml (56 mmol) of N,N-diisopropylethylamine were addedslowly dropwise to a suspension of 20.35 g (56 mmol) of zinc(II)trifluoromethanesulphonate in 300 ml of nitromethane at RT and themixture was stirred for 1 h thereafter. The yellow suspension wassubsequently admixed with 13.9 g (84 mmol) of(1R,2S)-(−)-2-(N-methylamino)-1-phenylpropan-1-ol[(−)-N-methylephedrine] and 18.4 g of molecular sieve and stirred for 1h thereafter, then cooled to −20° C. A dropping funnel was charged with51.0 g (186.6 mmol) of the compound from Example 11A, with addition of75 ml of nitromethane. The initial solution underwent spontaneouswarming to about 40° C., and the formation of a precipitate began.Thereafter the entire contents of the dropping funnel were addedimmediately in one portion to the cooled zinc(II)trifluoromethanesulphonate/(−)-N-methylephedrine mixture (no temperaturecontrol). The reaction mixture was stirred in a cooling bath (−20° C.)for a further 5 h, and then stirred overnight as well, the temperatureslowly rising to 0° C. The work-up was carried out in analogy tovariant 1. The crude product was purified using a short silica gelcolumn (eluent dichloromethane/ethanol 100:2). The product-containingfractions were combined and freed from the solvents on a rotaryevaporator, and the residue was dried in an HV. The solid obtained wasstirred with 200 ml of n-pentane at RT, isolated again by filtration anddried in an HV. This gave 32.4 g of the title compound (approximately82% purity according to LC-MS, 43% of theory).

Of this product, 5 g were purified via HPLC [Method 20]. This gave 3.87g of the title compound.

LC/MS [Method 5]: R_(t)=1.15 min; (ES neg.): m/z=333 (M−H)⁻.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 4.77 (dd, 1H), 4.97 (dd, 1H),5.34-5.44 (m, 1H), 7.59-7.66 (m, 1H), 7.66-7.74 (m, 2H), 7.78 (br. s,1H), 7.89 (br. d, 1H).

Example 101A tert-Butyl{2-amino-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate (non-racemicenantiomer mixture)

Of the compound from Example 100A, 3.87 g (11.2 mmol) were hydrogenatedin 230 ml of methanol with 5 ml of Raney nickel suspension (50% inwater) at a hydrogen pressure of 3 bar for 3 h. The reaction mixture wasfiltered over celite and washed with methanol, and the filtrate wasfreed from the solvent on a rotary evaporator. The residue was dried inan HV. This gave 3.50 g (99% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=0.76 min; m/z=305 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.37 (s, 9H), 2.64-2.76 (m, 2H), 3.33 (s,2H), 4.45-4.55 (m, 1H), 7.44 (br. d, 1H), 7.51-7.64 (m, 4H).

Example 102A tert-Butyl methyl{1-[3-(trifluoromethyl)phenyl]ethane-1,2-diyl}biscarbamate (non-racemicenantiomer mixture)

Of the compound from Example 101A, 500 mg (1.64 mmol) were introduced indichloromethane together with 320 μl (2.30 mmol) of triethylamine, withice cooling, and 152 μl (1.97 mmol) of methyl chloroformate were added.The ice bath was removed and the mixture was stirred for a further 1 h.The solvent was removed on a rotary evaporator and the residue waspurified by preparative HPLC [Method 20]. The product fractions werecombined and freed from the solvents on a rotary evaporator, and theresidue was dried in an HV. This gave 428 mg (72% of theory) of thetitle compound.

LC/MS [Method 2]: R_(t)=2.27 min; m/z=363 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 3.19-3.26 (m, 2H), 3.46 (br.s, 3H), 4.64-4.76 (m, 1H), 7.18 (br. t, 1H), 7.49 (br. d, 1H), 7.53-7.65(m, 4H).

Example 103A tert-Butyl ethyl{1-[3-(trifluoromethyl)phenyl]ethane-1,2-diyl}biscarbamate (non-racemicenantiomer mixture)

A solution of 500 mg (1.64 mmol) of the compound from Example 101A and321 μl (2.30 mmol) of triethylamine in 15 ml of dichloromethane wascooled to 0° C. and admixed with 189 μl (1.97 mmol) of ethylchloroformate. The ice bath was removed and the mixture was stirred fora further 1 h. The volatile constituents were removed on a rotaryevaporator and the residue was purified by preparative HPLC [Method 20].The product fractions were combined and freed from the solvents on arotary evaporator. The residue was dried in an HV. This gave 527 mg (85%of theory) of the title compound.

LC/MS [Method 2]: R_(t)=2.37 min; m/z=377 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.08 (t, 3H), 1.35 (s, 9H), 3.18-3.27 (m,2H), 3.85-3.97 (m, 2H), 4.65-4.77 (m, 1H), 7.13 (br. t, 1H), 7.48 (br.d, 1H), 7.52-7.64 (m, 4H).

Example 104A tert-Butyl{2-[(ethylcarbamoyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate(non-racemic enantiomer mixture)

A solution of 500 mg (1.64 mmol) of the compound from Example 101A in 15ml of dichloromethane was admixed at 0° C. with 260 μl (3.29 mmol) ofethyl isocyanate. The ice bath was removed and the reaction mixture wasstirred for a further 1 h. Then all of the volatile constituents wereremoved on a rotary evaporator. The residue was purified by preparativeHPLC [Method 23]. The product fraction was freed from the solvent on arotary evaporator. Drying of the residue in an HV gave 546 mg (89% oftheory) of the title compound.

LC/MS [Method 2]: R_(t)=2.16 min; m/z=376 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=0.95 (t, 3H), 1.35 (s, 9H), 2.91-3.04 (m,2H), 3.08-3.19 (m, 1H), 3.21-3.31 (m, 1H), 4.57-4.66 (m, 1H), 5.88 (br.t, 1H), 5.96 (br. t, 1H), 7.48-7.64 (m, 5H).

Example 105A 2-Bromoethyl tert-butyl{1-[3-(trifluoromethyl)phenyl]ethane-1,2-diyl}biscarbamate (non-racemicenantiomer mixture)

A solution of 272 mg (0.89 mmol) of the compound from Example 101A and171 μl (0.98 mmol) of N,N-diisopropylethylamine in 3 ml of acetonitrilewas admixed dropwise with a solution of 106 μl (0.98 mmol) of2-bromoethyl chloroformate in 2 ml of acetonitrile. For work-up, after10 minutes, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added. The organic phase was separated, washedagain with saturated aqueous sodium hydrogen carbonate solution, driedover sodium sulphate and freed from the volatile constituents on arotary evaporator. Drying of the residue in an HV gave 352 mg (82% oftheory) of the title compound.

LC/MS [Method 4]: R_(t)=1.15 min; m/z=455/457 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 3.25 (t, 2H), 3.56 (t, 2H),4.09-4.28 (m, 2H), 4.66-4.79 (m, 1H), 7.39 (br. t, 1H), 7.45-7.69 (m,5H).

Example 106A tert-Butyl{2-(2-oxo-1,3-oxazolidin-3-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate(non-racemic enantiomer mixture)

A solution of 352 mg (0.77 mmol) of the compound from Example 105A in 10ml of DMF was admixed with 34 mg (0.85 mmol) of sodium hydride (60% inmineral oil). The reaction mixture was stirred at RT overnight. Forpurification, 2 ml of 1N hydrochloric acid were added and the entiremixture was purified by preparative HPLC [Method 23]. The productfractions were combined and freed from the solvents on a rotaryevaporator. Drying of the residue in an HV gave 242 mg (84% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.19 min; m/z=275 (M+H-BOC)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.37 (s, 9H), 3.34-3.44 (m, 2H), 3.45-3.62(m, 2H), 4.12-4.23 (m, 2H), 4.85-4.95 (m, 1H), 7.55-7.66 (m, 3H), 7.69(d, 1H), 7.78 (br. s., 1H).

Example 107A tert-Butyl{2-(2-oxoimidazolidin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate(non-racemic enantiomer mixture)

An ice-cooled solution of 302 mg (0.99 mmol) of the compound fromExample 101A in 10 ml of dichloromethane was admixed dropwise with 99 μl(1.09 mmol) of 2-bromoethyl isocyanate. After 10 minutes, the ice bathwas removed and the mixture was stirred for a further 5 min. All of thevolatile components were removed on a rotary evaporator. The residue wastaken up in 5 ml of anhydrous THF and admixed, with ice cooling, with 44mg of sodium hydride (60% in mineral oil, 1.09 mmol). After 2 h, 1 ml of1M hydrochloric acid was added and the reaction mixture was freed fromthe solvent on a rotary evaporator. The aqueous residue was dissolved inDMSO and purified by preparative HPLC [Method 23]. The product fractionwas freed from the solvents on a rotary evaporator. Drying of theresidue in an HV gave 210 mg (38% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=0.84+0.99 min; m/z=374 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (br. s., 9H), 3.09-3.18 (m, 2H),3.18-3.32 (m, 4H), 4.74-4.86 (m, 1H), 6.25-6.39 (br. s, 1H), 7.44-7.76(m, 5H).

Example 108A tert-Butyl{2-(methylsulphinyl)-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate(racemic diastereomer mixture)

A solution of 780 μl (11.0 mmol) of dimethyl sulphoxide in 30 ml of THFwas admixed slowly at −78° C. with 6.9 ml of n-butyllithium solution(1.6M in hexane, 11.0 mmol). The resulting suspension was stirred at−78° C. for 30 min and then added to a solution, cooled to −78° C.beforehand, of 1 g (3.66 mmol) of the compound from Example 15A in 30 mlof THF. The reaction mixture was stirred at −78° C. for 30 min more andthen slowly warmed to RT. After 30 min at RT, it was again cooled to−20° C. and the reaction was halted by addition of 20 ml of 10% strengthaqueous ammonium chloride solution. The mixture was diluted with ethylacetate. The organic phase was separated, washed twice with water andonce with saturated aqueous sodium chloride solution, dried over sodiumsulphate and freed from the volatile constituents on a rotaryevaporator. The residue was purified by preparative HPLC [Method 20].The product fraction was freed from the solvents on a rotary evaporator.Drying of the residue in an HV gave 952 mg (74% of theory) of the titlecompound as a diastereomer mixture.

LC/MS [Method 5]: R_(t)=0.92+0.95 min; m/z=352 (M+H)⁺.

Example 109A tert-Butyl{2-(methylsulphanyl)-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate(racemate)

Of the compound from Example 108A, 400 mg (1.14 mmol), and 567 mg (2.16mmol) of triphenylphosphine, were dissolved in 14 ml oftetrachloromethane. The reaction mixture was stirred overnight at refluxtemperature and then freed from the solvent on a rotary evaporator. Theresidue was purified by preparative HPLC [Method 20]. The productfraction was freed from the solvent on a rotary evaporator. Drying in anHV gave 340 mg (85% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.20 min; m/z=336 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 2.08 (s, 3H), 2.62 (dd, 1H),2.71 (dd, 1H), 5.04-5.14 (m, 1H), 7.47 (t, 1H), 7.58 (br. d, 1H),7.64-7.72 (m, 2H), 7.76 (br. d, 1H).

Example 110A tert-Butyl[(2-chlorophenyl)(phenylsulphonyl)methyl]carbamate

Quantities of 2.78 g (23.7 mmol) of tert-butyl carbamate and 7.79 g(47.4 mmol) of benzenesulphinic acid sodium salt were introduced in 55ml of methanol/water 1:2 at RT and admixed with 5 g (35.6 mmol) of2-chlorobenzaldehyde and then with 1.78 ml (47.1 mmol) of formic acid.The mixture was stirred at RT for 2 days. The white solid precipitatedwas filtered off with suction and washed in succession twice each withwater and diethyl ether. Drying in an HV gave 5.77 g (42% of theory) ofthe title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.21 (s, 9H), 6.54 (d, 1H), 7.42-7.58 (m,3H), 7.62-7.70 (m, 2H), 7.73-7.79 (m, 1H), 7.82 (d, 2H), 7.92-8.03 (m,1H), 8.87 (d, 1H).

Example 111A tert-Butyl [(E)-(2-chlorophenyl)methylene]carbamate

A quantity of 12.53 g (90.7 mmol) of potassium carbonate was heatedthrough in an HV and then cooled under an argon atmosphere. Quantitiesof 140 ml of anhydrous THF and 5.77 g (15.1 mmol) of the compound fromExample 110A were added and the mixture was stirred under an argonatmosphere at reflux temperature for 16 h. After cooling to RT, thereaction mixture was filtered over celite. The solid was washed with alittle THF. The entire filtrate was freed from the solvent on a rotaryevaporator. The oily residue was dried in an HV. This gave 3.55 g (98%of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.52 (s, 9H), 7.47-7.53 (m, 1H), 7.61-7.69(m, 2H), 8.05 (d, 1H), 9.10 (s, 1H).

Example 112A tert-Butyl [1-(2-chlorophenyl)-2-nitroethyl]carbamate(racemate)

A quantity of 16 ml (295.41 mmol) of nitromethane was admixed with 436μl (2.50 mmol) of N,N-diisopropylethylamine and the yellow solution wasstirred at RT for 1 h. Then 2.0 g (8.34 mmol) of the compound fromExample 111A were added and the mixture was stirred overnight at RT. Allof the volatile constituents were removed on a rotary evaporator. Theresidue was dissolved in 9 ml of isopropanol in the heat of boiling, andthe solution was then cooled to 0° C. The white solid precipitated wasfiltered off with suction and washed with a little cold isopropanol.Drying in an HV gave 1.18 g (47% of theory) of the title compound.

The mother liquor was concentrated under reduced pressure and theresidue was purified by preparative HPLC [Method 23]. The productfraction was freed from the solvents on a rotary evaporator and dried inan HV. This gave a further 0.90 g (36% of theory) of the title compound.

LC/MS [Method 2]: R_(t)=2.30 min; m/z=301 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.35 (s, 9H), 4.62 (dd, 1H), 4.81 (dd, 1H),5.73 (dt, 1H), 7.32-7.44 (m, 2H), 7.49 (dd, 1H), 7.54 (dd, 1H), 8.00 (d,1H).

Example 113A tert-Butyl [2-amino-1-(2-chlorophenyl)ethyl]carbamate

In the same way as for Example 33A, from 1.0 g (3.33 mmol) of thecompound from Example 112A, the title compound was obtained: 993 mg(quantitative).

LC/MS [Method 4]: R_(t)=0.68 min; m/z=271 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 1.65 (br. s., 2H), 2.58 (dd,1H), 2.72 (dd, 1H), 4.79-4.87 (m, 1H), 7.24 (dt, 1H), 7.32 (t, 1H),7.35-7.40 (m, 2H), 7.45 (br. d, 1H).

Example 114A tert-Butyl[2-(carbamoylamino)-1-(2-chlorophenyl)ethyl]carbamate

Of the compound from Example 113A, 330 mg (1.15 mmol) in 12 ml ofwater/methanol 1:1 were admixed at RT with 279 mg (3.44 mmol) ofpotassium cyanate. The mixture was heated at 40° C. for 1 h and thenadmixed with 1.15 ml of 1M hydrochloric acid (1.15 mmol) and stirredovernight at RT. A further 93 mg (1.14 mmol) of potassium cyanate wereadded and the mixture was stirred further at RT for 3 h. The entirereaction mixture was purified by preparative HPLC [Method 10]. Theproduct fraction was freed from the solvents on a rotary evaporator.Drying of the residue in an HV gave 292 mg (80% of theory) of the titlecompound.

LC/MS [Method 4]: R_(t)=0.86 min; m/z=314 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.35 (s, 9H), 3.03-3.13 (m, 1H), 3.19-3.29(m, 1H), 4.84-4.94 (m, 1H), 5.56 (br. s, 2H), 6.01-6.08 (m, 1H), 7.26(dt, 1H), 7.33 (t, 1H), 7.37-7.43 (m, 2H), 7.52 (br. d, 1H).

Example 115A tert-Butyl{1-(2-chlorophenyl)-2-[(methylsulphonyl)amino]ethyl}carbamate

A solution of 330 mg (1.15 mmol) of the compound from Example 113A in 7ml of pyridine was admixed at RT with 177 μl (2.29 mmol) ofmethanesulphonyl chloride. After 1 h the volatile constituents wereremoved on a rotary evaporator. The residue is purified by preparativeHPLC [Method 23]. The product fraction was freed from the solvents on arotary evaporator. Drying of the residue in an HV gave 312 mg (78% oftheory) of the title compound.

LC/MS [Method 4]: R_(t)=0.96 min; m/z=349 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.37 (s, 9H), 2.82 (s, 3H), 3.08 (ddd, 1H),3.14-3.23 (m, 1H), 5.01-5.10 (m, 1H), 7.21 (t, 1H), 7.29 (dt, 1H), 7.35(br. t, 1H), 7.41 (dd, 1H), 7.44 (br. d, 1H), 7.50 (dd, 1H).

Example 116A tert-Butyl{1-(2-chlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}carbamate

From 330 mg (1.15 mmol) of the compound from Example 113A and 217 μl(2.29 mmol) of ethanesulphonyl chloride, in the same way as for Example115A, 263 mg (63% of theory) of the title compound were obtained.

LC/MS [Method 4]: R_(t)=1.01 min; m/z=363 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.14 (t, 3H), 1.37 (s, 9H), 2.84-3.00 (m,2H), 3.07 (ddd, 1H), 3.12-3.22 (m, 1H), 4.99-5.08 (m, 1H), 7.23-7.31 (m,2H), 7.32-7.38 (m, 1H), 7.41 (dd, 1H), 7.42 (br. d, 1H), 7.49 (dd, 1H).

Example 117A tert-Butyl[1-(2-chlorophenyl)-2-(methylsulphonyl)ethyl]carbamate

A solution of 1 g (10.6 mmol) of (methylsulphonyl)methane in 30 ml ofTHF was cooled to −78° C. and admixed slowly with 6.65 ml ofn-butyllithium solution (1.6M in hexane, 10.6 mmol). After 30 min at−78° C., the suspension obtained was added to a solution, cooled to −78°C. beforehand, of 850 mg (3.55 mmol) of the compound from Example 111Ain 20 ml of THF. The reaction mixture was stirred at −78° C. for afurther 30 min and then slowly warmed to RT. After 30 min, it was cooledto −20° C. again and the reaction was halted by addition of 20 ml of 10%strength aqueous ammonium chloride solution. The mixture was dilutedwith ethyl acetate. The organic phase was separated and washed twicewith water and once with saturated aqueous sodium chloride solution. Theorganic phase was dried over sodium sulphate, filtered and freed fromthe solvent on a rotary evaporator. The residue was stirred with 10 mlof methanol/water 10:1 and the solid was filtered off with suction. Theslightly yellowish solid was stirred with 20 ml of pentane/isopropanol5:1, then filtered off with suction again. Drying in an HV gave 800 mg(55% of theory) of the title compound (82% purity according to LC/MS).

LC/MS [Method 3]: R_(t)=1.08 min; m/z=234 (M+H-BOC)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 3.01 (s, 3H), 3.19-3.28 (m,1H), 3.43-3.55 (m, 1H), 5.47-5.54 (m, 1H), 7.28-7.35 (m, 1H), 7.38 (t,1H), 7.45 (d, 1H), 7.51 (d, 1H), 7.82 (br. d, 1H).

Example 118A tert-Butyl[1-(2-chlorophenyl)-2-(methylsulphinyl)ethyl]carbamate (racemicdiastereomer mixture)

In the same way as for Example 108A, from 850 mg (3.55 mmol) of thecompound from Example 111A, the title compound was obtained: 697 mg (62%of theory).

LC/MS [Method 4]: R_(t)=0.87+0.88 min; m/z=318 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 2.55 (br. s., “1.5H” (3Hfirst diastereomer)), 2.64 (s, “1.5H” (3H second diastereomer)),2.81-3.15 (m, 2H), 5.22-5.38 (m, 1H), 7.31 (br. t, 1H), 7.35-7.50 (m,3H), 7.54 (br. d, 1H), 7.75-7.87 (m, 1H).

Example 119A tert-Butyl[1-(2-chlorophenyl)-2-(methylsulphanyl)ethyl]carbamate (racemate)

In the same way as for Example 109A, 100 mg (0.32 mmol) of the compoundfrom Example 118A were reduced. This gave 44 mg (45% of theory) of thetitle compound.

LC/MS [Method 5]: R_(t)=1.20 min; m/z=302 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.37 (s, 9H), 2.11 (s, 3H), 2.59-2.72 (m,2H), 5.05-5.17 (m, 1H), 7.27 (dt, 1H), 7.35 (t, 1H), 7.41 (dd, 1H), 7.49(dd, 1H), 7.57 (br. d, 1H).

Example 120A tert-Butyl{2-(methylsulphonyl)-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate

From 1.03 g (11.0 mmol) of (methylsulphonyl)methane and 1.0 g (3.7 mmol)of the compound from Example 15A, in the same way as for Example 117A,1.11 g (82% of theory) of the title compound were obtained.

LC/MS [Method 3]: R_(t)=1.12 min; m/z=268 (M+H-BOC)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.35 (s, 9H), 2.99 (s, 3H), 3.19 (br. d,1H), 3.58 (dd, 1H), 5.53 (br. t, 1H), 7.50 (t, 1H), 7.67-7.80 (m, 3H),7.85 (br. d, 1H).

Example 121A tert-Butyl{2-(methylsulphonyl)-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate

From 1.50 g (15.9 mmol) of (methylsulphonyl)methane and 1.45 g (5.31mmol) of the compound from Example 11A, using the same process as forExample 117A, 535 mg (27% of theory) of the title compound wereobtained.

LC/MS [Method 4]: R_(t)=1.02 min; m/z=368 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 2.99 (s, 3H), 3.48-3.64 (m,2H), 5.17 (m, 1H), 7.56-7.70 (m, 3H), 7.70-7.78 (m, 2H).

Example 122A tert-Butyl{2-(dimethylsulphamoyl)-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate

A solution of 676 mg (5.49 mmol) of N,N-dimethylmethanesulphonamide in10 ml of THF was admixed slowly at −78° C. with 3.43 ml (5.49 mmol) of1.6M n-butyllithium solution in hexane versetzt. After 30 min at −78°C., the colourless solution obtained was added to a solution, cooled to−78° C. beforehand, of 500 mg (1.83 mmol) of the compound from Example11A in 10 ml of THF. The reaction mixture was stirred at −78° C. for 30min more and then slowly warmed to RT. After 30 min it was cooled to−20° C. again and the reaction was halted by addition of 5 ml of 10%strength aqueous ammonium chloride solution. The mixture was dilutedwith ethyl acetate and then washed twice with water and once withsaturated aqueous sodium chloride solution. The organic phase was driedover sodium sulphate and freed from the solvent on a rotary evaporator.The residue was purified by preparative HPLC [Method 23]. The productfraction was freed from the solvent on a rotary evaporator. Drying ofthe residue in an HV gave 296 mg (41% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=1.28 min; m/z=297 (M+H-BOC)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 2.76 (s, 6H), 3.33 (dd, 1H),3.53 (dd, 1H), 5.01-5.11 (m, 1H), 7.56-7.69 (m, 4H), 7.71 (br. s, 1H).

Example 123A tert-Butyl methyl[1-(2,3-dichlorophenyl)ethane-1,2-diyl]biscarbamate

A solution of 192 mg (0.63 mmol) of the compound from Example 40A in 5.7ml of dichloromethane together was admixed at RT with 123 μl (0.88 mmol)of triethylamine and then with 58 μl (0.75 mmol) of methylchloroformate. The reaction mixture was stirred at RT overnight and thenall of the volatile constituents were removed on a rotary evaporator.The residue was taken up in DMSO and purified by preparative HPLC[Method 20]. The product fraction was freed from the solvents on arotary evaporator and dried in an HV. This gave 167 mg (73% of theory)of the title compound.

LC/MS [Method 3]: R_(t)=1.22 min; m/z=263 (M+H-BOC)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.14-3.27 (m, 2H), 3.48 (s, 3H), 5.07 (br.q, 1H), 7.13-7.21 (m, 1H), 7.32-7.38 (m, 1H), 7.38-7.44 (m, 1H), 7.47(br. d, 1H), 7.53 (dd, 1H).

Example 124A tert-Butyl ethyl[1-(2,3-dichlorophenyl)ethane-1,2-diyl]biscarbamate

From 192 mg (629 μmol) of the compound from Example 40A and 72 μl (755μmol) of ethyl chloroformate, in the same way as for Example 123A, 184mg (78% of theory) of the title compound were prepared.

LC/MS [Method 3]: R_(t)=1.29 min; ES⁺: m/z=277 (M+H-BOC)⁺. ES⁻: m/z=375(M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=7.31-7.57 (m, 4H), 7.12 (br. t., 1H), 5.07(q, 1H), 3.88-3.98 (m, 2H), 3.12-3.28 (m, 2H), 1.35 (m, 9H), 1.10 (t,3H).

Example 125A tert-Butyl[2-(carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]carbamate

Of the compound from Example 40A, 192 mg (0.63 mmol) were introduced in11 ml of water/methanol 1:2 and admixed in succession at RT with 0.63 ml(0.63 mmol) of 1M hydrochloric acid and 166 mg (2.05 mmol) of potassiumcyanate. The reaction mixture was stirred at RT overnight and then freedfrom the methanol on a rotary evaporator. The residue was taken up inDMSO and purified by preparative HPLC [Method 20]. The product fractionwas concentrated on a rotary evaporator. Drying of the residue in an HVgave 177 mg (73% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=1.05 min; m/z=348 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.34 (s, 9H), 3.04-3.19 (m, 1H), 3.19-3.30(m, 1H), 4.86-4.99 (m, 1H), 5.57 (br. s., 2H), 6.02-6.16 (br.m, 1H),7.31-7.42 (m, 2H), 7.47-7.57 (m, 1H), 7.61 (d, 1H).

Example 126A tert-Butyl{1-(2,3-dichlorophenyl)-2-[(ethylcarbamoyl)amino]ethyl}carbamate

A solution of 192 mg (0.63 mmol) of the compound from Example 40A in 5.7ml of dichloromethane was admixed at RT with 100 μl (1.26 mmol) of ethylisocyanate. The reaction mixture was stirred overnight at RT and thenfreed from the solvent on a rotary evaporator. The residue was taken upin DMSO and purified by preparative HPLC [Method 20]. The productfraction was freed from the solvents on a rotary evaporator. Drying ofthe residue in an HV gave 173 mg (73% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=1.16 min; m/z=276 (M+H-BOC)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=0.96 (t, 3H), 1.34 (s, 9H), 2.89-3.07 (m,2H), 3.07-3.19 (m, 1H), 3.23-3.32 (m, 2H), 4.88-4.99 (m, 1H), 5.88-6.01(m, 2H), 7.31-7.43 (m, 2H), 7.48-7.56 (m, 1H), 7.60 (br. d, 1H).

Example 127A 3-Amino-3-[3-(trifluoromethyl)phenyl]propan-1-ol

With ice cooling and under argon, 10.9 ml (10.94 mmol) ofborane-tetrahydrofuran complex (1M in THF) were introduced. Then 850 mg(3.65 mmol) of 3-amino-3-[3-(trifluoromethyl)phenyl]propanoic acid wereadded. After 5 minutes, the cooling bath was removed and the mixture wasstirred at RT overnight and for 4 h at reflux. After cooling to RT,pieces of ice were added until the evolution of gas came to an end. Themixture was rendered alkaline with 1M aqueous sodium hydroxide solution,diluted with water to a volume of approximately 150 ml, and extractedthree times with dichloromethane. The combined organic phases were driedover sodium sulphate, filtered and freed from the solvent on a rotaryevaporator. Drying in an HV gave 744 mg (85% of theory) of the titlecompound in 92% purity.

LC/MS [Method 4]: R_(t)=0.45 min; m/z=220 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.71 (s, 1H), 7.60-7.67 (m, 1H), 7.49-7.58(m, 2H), 4.55 (br.s, 1H), 3.97-4.04 (dd, 1H), 3.34-3.50 (m, 2H), 2.00(br. s., 2H), 1.59-1.78 (m, 2H).

Example 128A tert-Butyl{3-hydroxy-1-[3-(trifluoromethyl)phenyl]propyl}carbamate

A solution of 744 mg (3.39 mmol) of the compound from Example 127A in 30ml of dichloromethane was admixed with 1.56 ml (6.79 mmol) ofdi-tert-butyl dicarbonate and stirred at RT for 3 h. For work-up, thereaction mixture was diluted with 100 ml of ethyl acetate and washed insuccession twice each with 1M hydrochloric acid, saturated aqueoussodium hydrogen carbonate solution and saturated aqueous sodium chloridesolution. The organic phase was dried over sodium sulphate and freedfrom the solvent on a rotary evaporator. The residue was purified bypreparative HPLC [Method 23]. The product fraction was freed from thesolvents on a rotary evaporator and the residue was dried in an HV. Thisgave 870 mg (80% of theory) of the title compound.

LC/MS [Method 5]: R_(t)=1.03 min; m/z=320 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆) (principal rotamer): δ=7.52-7.67 (m, 4H), 7.49(d, 1H), 4.70 (q, 1H), 4.53 (t, 1H), 3.35-3.45 (m, 1H), 3.23-3.30 (m,1H), 1.79-1.90 (m, 1H), 1.64-1.78 (m, 1H), 1.44 (s, 9H).

Example 129A 3-Amino-3-[3-(trifluoromethyl)phenyl]propyl carbamate

Of the compound from Example 128A, 827 mg (2.59 mmol) were introduced in100 ml of acetonitrile. A solution of 676 μl (7.77 mmol) ofchlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwiseat −15° C. After 5 min, 50 ml of water were added and the mixture wasthen stirred at 60° C. overnight. The reaction mixture was admixed withsaturated aqueous sodium hydrogen carbonate solution and then extractedthree times with ethyl acetate. The combined organic phases were driedover sodium sulphate and freed from the solvent on a rotary evaporator.Drying of the residue in an HV gave 678 mg (quant.) of the titlecompound.

LC/MS [Method 2]: R_(t)=1.06 min; m/z=263 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.72 (s, 1H), 7.64 (d, 1H), 7.51-7.61 (m,2H), 6.43 (br. s, 2H), 3.90-4.01 (m, 2H), 3.82 (dt, 1H), 3.30 (s, 2H),1.73-1.93 (m, 2H).

Example 130A Ethyl amino[3-(difluoromethyl)phenyl]acetate

Quantities of 1.0 g (4.83 mmol) of 3-(difluoromethyl)phenyl bromide,1.42 g (5.31 mmol) of ethyl N-(diphenylmethylene)glycinate, 0.19 ml(0.193 mmol) of a 1M solution of tri-tert-butylphosphane in toluene, 55mg (0.10 mmol) of bis(dibenzylideneacetone)palladium(0), 3.08 g (14.49mmol) of potassium phosphate and 6.04 ml (18.11 mmol) of 3M hydrochloricacid were heated under argon to 100° C. in 20 ml of degassed toluene,and stirred at this temperature overnight. A further 0.19 ml (0.193mmol) of tri-tert-butylphosphane (1M solution in toluene) and 55 mg(0.10 mmol) of bis(dibenzylideneacetone)palladium(0) were added and themixture was stirred at 100° C. for a further 24 h. The mixture wascooled to RT and filtered over celite. The celite was washed with alittle toluene and the filtrate was freed from the solvent under reducedpressure. For elimination of the protecting group, the residue was takenup in 50 ml of acetonitrile and admixed with 15 ml of 3M hydrochloricacid. After 2 h, the acetonitrile fraction was removed on a rotaryevaporator. The aqueous residue was diluted with water to a volume ofapproximately 150 ml and washed three times with diethyl ether. Theaqueous phase was adjusted to a pH of 9 using 2M aqueous sodiumcarbonate solution and then extracted three times with dichloromethane.The combined organic phases were dried over sodium sulphate, filteredand freed from the solvent on a rotary evaporator. Drying in an HV gave265 mg (6.46% of theory) of the title compound, in a purity of about27%, which was reacted further without additional purification.

LC/MS [Method 3]: R_(t)=0.63 min; m/z=230 (M+H)⁺.

Example 131A Ethyl[(tert-butoxycarbonyl)amino][3-(difluoromethyl)phenyl]acetate

Of the compound from Example 130A, 265 mg (1.16 mmol) were stirred in10.2 ml of dichloromethane with 505 mg (2.31 mmol) of di-tert-butyldicarbonate at RT for 3 h. The solvent was then removed on a rotaryevaporator. The residue was purified by preparative HPLC [Method 20, andagain by Method 23]. The product fraction was freed from the solvent ona rotary evaporator and the residue was dried in an HV. This gave 62 mg(29% of theory) of the title compound in a purity of about 49%.

LC/MS [Method 2]: R_(t)=2.42 min; m/z=330 (M+H)⁺.

Example 132A tert-Butyl{1-[3-(difluoromethyl)phenyl]-2-hydroxyethyl}carbamate

At RT, 11.97 mg (0.28 mmol) of lithium chloride and 10.68 mg (0.28 mmol)of sodium borohydride were stirred in 0.25 ml of ethanol for 15 min.Then the mixture was cooled to 0° C. and a solution of 62 mg (about 0.09mmol, purity 49%) of the compound from Example 131A in 0.25 ml oftetrahydrofuran was added dropwise. The mixture was stirred overnight atRT. For work-up, it was cooled with ice-water and adjusted to a pH of 2using 1M hydrochloric acid. The reaction mixture was purified bypreparative HPLC [Method 20]. The product fraction was freed from thesolvent on a rotary evaporator and dried in an HV. This gave 56 mg(about 45% purity, 93% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (br. s, 9H), 3.45-3.56 (m, 2H),4.49-4.64 (m, 1H), 4.82 (t, 1H), 7.01 (t, J_(H-F)=56 Hz, 1H), 7.18-7.53(m, 4H).

Example 133A tert-Butyl({2-[(tert-butoxycarbonyl)amino]-2-[3-(trifluoromethyl)phenyl]ethyl}sulphamoyl)-carbamate

A solution of 110 mg (1.48 mmol) of tert-butanol in 2 ml ofdichloromethane was cooled to 0° C. and admixed dropwise with a solutionof 129 μl (1.48 mmol) of chlorosulphonyl isocyanate in 2 ml ofdichloromethane. The mixture was stirred at RT for 1 h. In a syringe,820 μl of this solution were taken and were added dropwise to a solutionof 90 mg (296 μmol) of the compound from Example 22A in 2 ml ofdichloromethane. Then 103 μl of N,N-diisopropylethylamine were added andthe reaction mixture was stirred further at RT for 2 h. The volatileconstituents were removed on a rotary evaporator. The residue wasdissolved in a little acetonitrile and admixed with 1 ml of 1Mhydrochloric acid, and the solution obtained was purified by preparativeHPLC [Method 23]. The product-containing fraction was freed from thesolvents on a rotary evaporator and the residue was dried in an HV. Thisgave 111 mg (76% of theory) of the title compound.

LC/MS [Method 5]: R_(t)=1.16 min; m/z=484 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.36 (s, 9H), 1.41 (s, 9H), 3.08-3.23 (m,2H), 4.70-4.82 (m, 1H), 7.50 (br. d, 1H), 7.54-7.72 (m, 5H), 10.91 (br.s, 1H).

Example 134A N-{2-Amino-2-[3-(trifluoromethyl)phenyl]ethyl}sulphuricdiamide

A solution of 100 mg (0.20 mmol) of the compound from Example 133A in 2ml of dichloromethane was admixed with 2 ml of a 4M solution of hydrogenchloride in dioxane, and the mixture was stirred at RT for 2 h. It wasdiluted with ethyl acetate and admixed with 10% strength aqueous sodiumhydrogen carbonate solution. The alkaline aqueous phase was extractedtwice with ethyl acetate. The combined organic phases were dried oversodium sulphate and freed from the solvents on a rotary evaporator. Theresidue was the title compound (53 mg, 92% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ=ca. 2.66 (br. s, 2H), 2.86-2.99 (m, 1H),2.99-3.12 (m, 1H), 4.09 (dd, 1H), 6.60 (br. s, 3H), 7.52-7.64 (m, 2H),7.68 (br. d, 1H), 7.75 (br. s, 1H).

Example 135A tert-Butyl{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}methylcarbamate

A quantity of 438 ml of borane-tetrahydrofuran complex (1M solution inTHF, 438 mmol) was introduced with ice cooling. Then 35 g (110 mmol) ofN-Boc-2-(3-trifluoromethylphenyl)-DL-glycine were added in portions. Thereaction mixture was stirred at RT for 2 h and then cautiously admixedwith pieces of ice. After the end of the evolution of gas, the solventwas removed on a rotary evaporator. The aqueous residue was admixed withsaturated sodium hydrogen carbonate solution and extracted three timeswith ethyl acetate. The combined organic phases were dried over sodiumsulphate and freed from the solvent on a rotary evaporator. The residuewas taken up in acetonitrile and 2.5% strength aqueous sodium hydrogencarbonate solution. Then 25.18 ml (109.62 mmol) of di-tert-butyldicarbonate were added and the mixture was stirred at RT for 3 h. Theacetonitrile was removed on a rotary evaporator. The residue wasextracted three times with ethyl acetate, dried over sodium sulphate,filtered and freed from the solvent on a rotary evaporator. The residuewas again admixed with 438 ml of borane-tetrahydrofuran complex (1Msolution in THF, 438 mmol) and stirred at 70° C. for 3 h. It was workedup again, and an excess of a 4N solution of hydrogen chloride in dioxanewas added to the complete work-up mixture, which was stirred overnight.Thereafter the solvent was removed on a rotary evaporator. The residuewas dried in an HV and then admixed once again with 400 ml ofborane-tetrahydrofuran complex (1M solution in THF, 400 mmol) andstirred overnight. It was then worked up and again, as described above,reacted with 25.18 ml (109.62 mmol) of di-tert-butyl dicarbonate. Thecrude product obtained after work-up was purified by preparative HPLC.Drying in an HV gave 10.2 g (29% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=1.24 min; m/z=220 (M+H-BOC)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.53-7.68 (m, 4H), 5.20 (br.s, 0.5H(rotamer)), 5.04 (t, 1H), 5.03 (br. s, 0.5H (rotamer)), 3.77-3.98 (m,2H), 2.60-2.83 (br.s, 3H), 1.37 (br. s, 9H).

Example 136A tert-Butyl{2-(sulphamoyloxy)-1-[3-(trifluoromethyl)phenyl}ethyl]carbamate

A quantity of 171 μl (1.97 mmol) of chlorosulphonyl isocyanate wasadmixed under argon at 0° C., with vigorous stirring, with 74 μl (1.97mmol) of anhydrous formic acid. Following the addition, the reactionmixture solidified within seconds. A quantity of 2 ml of dichloromethanewas added. The reaction mixture was then stirred further at 0° C. for 1h and then RT for 8 h. Thereafter it was cooled to 0° C. again andadmixed with a solution of 400 mg (1.31 mmol) of the compound fromExample 59A and 159 μl (1.97 mmol) of pyridine in 2 ml ofdichloromethane. The cooling bath was removed and the reaction mixturewas stirred overnight at RT. For work-up, 5 ml of water and 5 ml ofethyl acetate were added. After 10 min, the mixture was diluted with 100ml of ethyl acetate, and washed twice with water and once with saturatedaqueous sodium chloride solution. The organic phase was dried oversodium sulphate and freed from the solvent on a rotary evaporator. Theresidue was purified by preparative HPLC [Method 10]. The productfraction was freed from the solvent on a rotary evaporator. Drying in anHV gave 260 mg (52% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=1.21 min; ESIneg.:m/z=383 (M−H)⁻.

H-NMR (400 MHz, DMSO-d₆): δ=7.67 (s, 5H), 7.55 (s, 2H), 4.96 (d, 1H),4.08-4.18 (m, 2H), 1.21-1.44 (m, 9H).

Example 137A Ethyl {2-amino-2-[3-(trifluoromethyl)phenyl]ethyl}carbamatehydrochloride (non-racemic enantiomer mixture)

A solution of 527 mg (1.40 mmol) of the compound from Example 103A in9.6 ml of dichloromethane was admixed at RT with 9.4 ml (37 mmol) of 4Mhydrogen chloride in dioxane and stirred for 1 h. Then all of thevolatile constituents were removed on a rotary evaporator. Drying of theresidue in an HV gave 437 mg (94% of theory) of the title compound.

LC/MS [Method 2]: R_(t)=1.31 min; m/z=277 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.09 (t, 3H), 3.38-3.59 (m, 2H), 3.95 (q,2H), 4.41-4.51 (m, 1H), 7.31 (br. t, 1H), 7.64-7.72 (m, 1H), 7.73-7.81(m, 2H), 7.87 (br. s, 1H), 8.56 (br. s, 3H).

In the same way as for Example 137A, the following examples wereprepared. The yields are in each case more then 94% of theory:

Analysis Example Reactant ¹H-NMR (400 MHz, No. Name and Structure No.DMSO-d₆) 138A

102A LC/MS [Method 2]: R_(t) = 1.16 min; m/z = 263 (M + H)⁺. ¹H-NMR: δ =3.40-3.59 (m, 2H), 3.50 (s, 3H), 4.42-4.51 (m, 1H), 7.37 (br. t, 1H),7.65- 7.72 (m, 1H), 7.74-7.81 (m, 2H), 7.89 (br. s, 1H), 8.62 (br. s,3H). 139A

104A LC/MS [Method 2]: R_(t) = 1.18 min; m/z = 276 (M + H)⁺. ¹H-NMR: δ =0.95 (t, 3H), 2.99 (q, 2H), 3.38-3.47 (m, 1H), 3.50-3.62 (m, 1H), 4.40-4.52 (m, 1H), 5.95-6.18 (br. s, 2H), 7.64-7.73 (m, 1H), 7.72-7.80 (m,2H), 7.87 (br. s, 1H), 8.45-8.66 (br m, 3H). 140A

106A LC/MS [Method 3]: R_(t) = 0.56 min; m/z = 275 (M + H)⁺. ¹H-NMR: δ =3.43-3.56 (m, 3H), 3.67-3.75 (m, 1H), 4.18- 4.30 (m, 2H), 4.67-4.76 (m,1H), 7.72 (t, 1H), 7.81 (br. d, 1H), 7.86 (br. d, 1H), 8.00 (br. s, 1H),8.61 (br. s, 3H). 141A

107A ¹H-NMR: δ = 3.13-3.33 (m, 4H), 3.36-3.60 (m, 2H), 4.55- 4.70 (m,1H), 6.55 (br. s, 1H), 7.66-7.73 (m, 1H), 7.75- 7.81 (m, 1H), 7.82-7.89(m, 1H), 7.98 (br. s, 1H), 8.44- 8.69 (br. m, 3H). 142A

109A LC/MS [Method 5]: R_(t) = 0.61 min; m/z = 236 (M + H)⁺. ¹H-NMR: δ =2.07 (s, 3H), 3.02 (dd, 1H), 3.11 (dd, 1H), 4.55 (br. t, 1H), 7.65 (t,1H), 7.80-7.88 (m, 2H), 7.98 (d, 1H), 8.83 (br. s, 3H). 143A

114A LC/MS [Method 2]: R_(t) = 0.22 + 0.73 min; m/z = 214 (M + H)⁺.¹H-NMR: δ = 3.35-3.45 (m, 1H), 3.48-3.58 (m, 1H), 4.65- 4.75 (m, 1H),6.30 (br. s., 1H), 7.39-7.50 (m, 2H), 7.54 (dd, 1H), 7.74 (br. d, 1H),8.66 (br. s., 3H). (NH₂ presumably beneath the broad water signal(5.5-5.9 ppm)). 144A

115A ¹H-NMR: δ = 2.91 (s, 3H), 3.35-3.49 (m, 2H), 4.70- 4.77 (m, 1H),7.42-7.53 (m, 3H), 7.56 (dd, 1H), 7.77 (dd, 1H), 8.75 (br. s., 3H). 145A

116A ¹H-NMR: δ = 1.14 (t, 3H), 2.90-3.05 (m, 2H), 3.35- 3.49 (m, 2H),4.73 (t, 1H), 7.42-7.54 (m, 3H), 7.56 (dd, 1H), 7.76 (dd, 1H), 8.71 (br.s., 3H). 146A

117A LC/MS [Method 2]: R_(t) = 0.81 min; m/z = 234 (M + H)⁺. ¹H-NMR: δ =3.01 (s, 3H), 3.85 (dd, 1H), 3.96 (dd, 1H), 5.18 (t, 1H), 7.43-7.61 (m,3H), 7.78-7.85 (m, 1H), 8.81 (br. s, 3H). 147A

119A ¹H-NMR: δ = 2.06 (s, 3H), 2.99 (dd, 1H), 3.07 (dd, 1H), 4.79 (t,1H), 7.40-7.52 (m, 2H), 7.55 (dd, 1H), 7.76 (br. d, 1H), 8.72 (br. s,3H). 148A

120A LC/MS [Method 5]: R_(t) = 0.32 min; m/z = 268 (M + H)⁺. ¹H-NMR: δ =3.07 (s, 3H), 3.90-4.06 (m, 2H), 4.98 (dd, 1H), 7.68 (t, 1H), 7.80-7.91(m, 2H), 8.04 (d, 1H), 8.96 (br. s., 3H). 149A

121A LC/MS [Method 4]: R_(t) = 0.43 min; m/z = 268 (M + H)⁺. ¹H-NMR: δ =3.01 (s, 3H), 3.84 (dd, 1H), 4.03 (dd, 1H), 5.01 (t, 1H), 7.71 (t, 1H),7.82 (d, 1H), 7.91 (d, 1H), 8.03 (s, 1H), 8.75 (br. s., 3H). 150A

122A LC/MS [Method 4]: R_(t) = 0.60 min; m/z = 297 (M + H)⁺. ¹H-NMR: δ =2.72 (s, 6H), 3.73-3.88 (m, 2H), 4.87 (t, 1H), 7.70 (t, 1H), 7.80 (d,1H), 7.92 (d, 1H), 8.03 (s, 1H), 8.74 (br. s, 3H). 151A

123A LC/MS [Method 5]: R_(t) = 0.56 min; m/z = 263 (M + H)⁺. ¹H-NMR: δ =3.36-3.44 (m, 1H), 3.53 (s, 3H), 3.51-3.60 (m, 1H), 4.77-4.87 (m, 1H),7.41 (br. t, 1H), 7.51 (t, 1H), 7.66-7.76 (m, 2H), 8.67 (br. s., 3H).152A

124A LC/MS [Method 5]: R_(t) = 0.64 min; m/z = 277 (M + H)⁺. ¹H-NMR: δ =8.67 (br. s., 3H), 7.71 (d, 2H), 7.51(t, 1 H), 7.36 (t, 1H), 4.77-4.88(m, 1H), 3.86-4.07 (m, 2H), 3.50- 3.61 (m, 1H), 3.36-3.44 (m, 1H), 1.12(t, 3H). 153A

125A LC/MS [Method 5]: R_(t) = 0.35 min; m/z = 248 (M + H)⁺. ¹H-NMR: δ =3.36-3.45 (m, 1H), 3.50-3.62 (m, 1H), 4.71- 4.82 (m, 1H), 5.4-5.8 (verybroad s, 2H), 6.23 (br. t, 1H), 7.51 (t, 1H), 7.63-7.75 (m, 2H),8.53-8.73 (m, 3H). 154A

126A LC/MS [Method 5]: R_(t) = 0.55 min; m/z = 276 (M + H)⁺. ¹H-NMR: δ =0.96 (t, 3H), 2.90-3.09 (m, 2H), 3.36- 3.47 (m, 1H), 3.48-3.55 (m, 1H),4.78 (d, 1H), 6.05 (br. s., 1H), 6.13 (br. t, 1H), 7.45- 7.57 (m, 1H),7.62-7.75 (m, 2H), 8.49-8.77 (m, 3H). 155A

132A ¹H-NMR: δ = 3.66-3.81 (m, 2H), 4.32-4.44 (m, 1H), 5.56 (br. s, 1H),7.06 (t, 1H), 7.28- 7.77 (m, 4H), 8.39-8.64 (m, 3H). 156A

135A LC/MS [Method 5]: R_(t) = 0.41 min; m/z = 220 (M + H)⁺. ¹H-NMR: δ =9.51 (br. s, 3H), 7.98 (s, 1H), 7.88 (d, 1H), 7.76- 7.82 (d, 1H),7.66-7.73 (t, 1H), 5.69 (m, 1H), 4.42 (br. s, 1 H), 3.79-3.93 (m, 2H),3.57 (s, 1H), 2.42 (s, 3H). 157A

136A LC/MS [Method 2]: R_(t) = 1.07 min; m/z = 285 (M + H)⁺. ¹H-NMR: δ =8.84 (br. s., 2H), 7.98 (s, 1H), 7.61-7.92 (m, 5H), 4.85 (t, 1H),4.29-4.46 (m, 2H).

Example 158A5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Of the compound from Example 3A, 1.08 g (3.3 mmol) were dissolved in 11ml of N,N-dimethylacetamide. The solution was freed from atmosphericoxygen using reduced pressure, and saturated with argon. Added to thissolution under argon were 21 mg (0.033 mmol) of the ruthenium complexRuCl(p-cymene)[(S,S)-Ts-DPEN)] (CAS No. 192139-90-5). Then a mixture of0.63 ml (16.6 mmol) of formic acid and 0.27 ml (1.91 mmol) oftriethylamine was added and the resulting mixture was stirred in theabsence of air at RT for 48 h. For work-up, the mixture was introducedinto 10 ml of 0.1N hydrochloric acid, and extracted with twice 20 ml ofethyl acetate. The combined organic phases were washed with saturatedaqueous sodium hydrogen carbonate solution, dried over sodium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by chromatography on silica gel (eluents: 1. cyclohexane/ethylacetate 3:1, 2. cyclohexane/ethyl acetate 1:1). This gave 830 mg (81% oftheory) of the target compound.

The enantiomeric excess was determined chromatographically by Method 27cto be 96% ee.

(S)-Enantiomer: R_(t)=5.73 min (R)-Enantiomer: R_(t)=6.82 min Example159A [(tert-Butoxycarbonyl)amino](3-chloro-2-fluorophenyl)acetic acid

A quantity of 5 g (24.56 mmol) of 3-chloro-2-fluoro-DL-phenylglycine wassuspended in dioxane and 147 ml of 5% strength aqueous sodium hydrogencarbonate solution. Then 5.36 g (24.56 mmol) of di-tert-butyldicarbonate were added. The suspension was stirred at RT overnight.

Ethyl acetate was added to the white suspension, these components werestirred together, and the precipitate was filtered off with suction. Themother liquor was extracted. The aqueous phase was extracted once againwith ethyl acetate. The combined organic phases were dried over sodiumsulphate, filtered and concentrated on a rotary evaporator. Drying in anHV gave 0.59 g (7.7% of theory) of the title compound.

The aqueous phase was acidified with 1M hydrochloric acid and extractedtwice with ethyl acetate. The extracts were dried over sodium sulphate,filtered and concentrated on a rotary evaporator. Drying in an HV gave5.05 g (65.4% of theory) of the title compound.

LC/MS [Method 2]: R_(t)=2.08 min; m/z=204 (M+H)⁺.

Example 160A tert-Butyl[1-(3-chloro-2-fluorophenyl)-2-hydroxyethyl]carbamate

Of the compound from Example 159A, 2 g (6.59 mmol) were dissolved underargon in 20 ml of THF. The solution was then cooled to 0° C. and 0.918ml (6.59 mmol) of triethylamine and 0.94 ml (7.24 mmol) of isobutylchloroformate were added dropwise. The reaction mixture was subsequentlystirred at 0° C. for 1 h. Thereafter the suspension was filtered througha Seitz frit into a cooled flask, with washing with a little THF. Asecond flask was charged with 747 mg (19.76 mmol) of sodium borohydridein 3 ml of water, with ice cooling. With vigorous stirring, the filtratewas slowly added dropwise. After 1 h, the batch was carefully admixedwith saturated aqueous sodium hydrogen carbonate solution. It was thenextracted with 30 ml of ethyl acetate. The organic phase was washedagain once with saturated aqueous sodium hydrogen carbonate solution andonce with saturated aqueous sodium chloride solution. It was then driedover sodium sulphate, filtered and freed from the solvent on a rotaryevaporator. Drying in an HV gave 1.74 g (75% of theory) of the titlecompound in approximately 83% purity.

LC/MS [Method 5]: R_(t)=0.99 min; m/z=290 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ=1.43 (s, 9H), 1.90-1.98 (m, 1H), 3.78-3.93(m, 2H), 5.01-5.12 (m, 1H), 5.32-5.42 (m, 1H), 7.08 (t, 1H), 7.23 (t,1H), 7.30-7.37 (m, 1H).

Example 161A 2-Amino-2-(3-chloro-2-fluorophenyl)ethanol hydrochloride

Of the compound from Example 160A, 1.74 g (6.01 mmol) were introduced in20 ml of dichloromethane. A quantity of 22 ml (88.00 mmol) of 4Mhydrogen chloride in dioxane was added. After stirring at RT for 1 h,the reaction mixture was evaporated to dryness on a rotary evaporatorand dried in an HV. This gave 1.38 g (88% of theory) of the titlecompound in approximately 87% purity.

LC/MS [Method 5]: R_(t)=0.27 min; m/z=190 (M+H)⁺.

Example 162A 2-Amino-2-(3-chloro-2-fluorophenyl)ethyl carbamatehydrochloride

Of the compound from Example 160A, 243 mg (0.84 mmol) were introduced in10 ml of acetonitrile under argon. Then at −15° C. 102 μl (1.17 mmol) ofchlorosulphonyl isocyanate were added dropwise. After 30 min, thereaction solution was admixed with 20 ml of water and heated at 60° C.overnight. The reaction mixture was cooled and introduced into saturatedaqueous sodium hydrogen carbonate solution. It was then extracted withethyl acetate. The organic phase was dried over sodium sulphate,filtered and freed from the solvent on a rotary evaporator. The residuewas taken up in 4 ml of dichloromethane and admixed with 4 ml of a 4Msolution of hydrogen chloride in dioxane. A precipitate formedimmediately. After a subsequent stirring time of 10 min, the batch wasfreed from the solvent on a rotary evaporator. Drying in an HV gave 219mg (77% of theory) of the title compound in 79% purity.

LC/MS [Method 5]: R_(t)=0.27 min; m/z=233 (M+H)⁺.

Example 163A N-Allyl-2-(2-bromo-4-chlorobenzoyl)hydrazinecarboxamide

A quantity of 10.0 g (40.1 mmol) of 2-bromo-4-chlorobenzhydrazide wassuspended in 100 ml of THF at 50° C. and admixed with 3.59 ml (40.9mmol) of allyl isocyanate in solution in 50 ml of THF. Stirring wascontinued for 16 h at 50° C. The batch was then allowed to cool to RTand diluted with 50 ml of diethyl ether. The precipitated solid wasfiltered off with suction, washed with a little diethyl ether and driedin an HV. This gave 11.30 g (85% of theory) of the title compound.

LC/MS [Method 6]: R_(t)=1.81 min; m/z=332 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.69 (t, 2H), 5.04 (d, 1H), 5.16 (d, 1H),5.76-5.88 (m, 1H), 6.45 (t, 1H), 7.58 (s, 2H), 7.84 (s, 1H), 8.10 (s,1H), 10.07 (s, 1H).

Example 164A4-Allyl-5-(2-bromo-4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Of the compound from Example 163A, 11.3 g (33.98 mmol) were taken up in61 ml (183.47 mmol) of 3M aqueous sodium hydroxide solution and heatedunder reflux for 36 h. The batch was then cooled, the fine precipitatewas removed by filtration, and the filtrate was admixed, with icecooling, with 28 ml (169.88 mmol) of half-concentrated hydrochloric acidto a pH of 10. The batch was filtered with suction and the product wasdissolved out of the precipitate using methanol. The methanol wasremoved on a rotary evaporator. The residue was dried in an HV. Thisgave 9.78 g (69% of theory) of the title compound in 75% purity.

LC/MS [Method 2]: R_(t)=1.88 min; m/z=314 and 316 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ=4.19 (d, 2H), 4.93 (d, 1H), 5.09 (d, 1H),5.64-5.74 (m, 1H), 7.32 (d, 1H), 7.39-7.44 (m, 1H), 7.72 (s, 1H), 9.45(br. s., 1H).

Example 165A Methyl[4-allyl-3-(2-bromo-4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate

Of the compound from Example 164A, 9.78 g (about 23.32 mmol, purity 75%)were dissolved in 75 ml of acetonitrile. Then 3.55 g (25.65 mmol) ofpotassium carbonate and 2.46 ml (27.98 mmol) of methyl chloroacetatewere added. The mixture was stirred under reflux for 5 hours. Aftercooling, it was filtered with suction. The filtrate was concentrated alittle on a rotary evaporator and then diluted with 30 ml of ethylacetate and washed with 30 ml each of 1M hydrochloric acid and ofsaturated aqueous sodium chloride solution. The organic phase was driedover sodium sulphate, filtered and freed from the solvent on a rotaryevaporator. The residue was purified by chromatography on silica gel(elution: cyclohexane/ethyl acetate 2:1). This gave 7.1 g (79% oftheory) of the title compound.

LC/MS [Method 6]: R_(t)=2.37 min; m/z=386 (M+H)⁺.

Example 166A[4-Allyl-3-(2-bromo-4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid

Of the compound from Example 156A, 4 g (10.35 mmol) were taken up in 30ml of methanol and admixed with 15.5 ml (15.52 mmol) of 1M lithiumhydroxide solution. The mixture was stirred at RT for 2 h. Then thesolvent was removed on a rotary evaporator. The residue was diluted with100 ml of water, washed with 20 ml of ethyl acetate and then acidifiedusing 1M hydrochloric acid. It was then again extracted with 50 ml ofethyl acetate. The organic phase was dried over sodium sulphate,filtered, concentrated on a rotary evaporator and dried in an HV. Thisgave 3.61 g (94% of theory) of the title compound.

LC/MS [Method 3]: R_(t)=0.99 min; m/z=372 and 374 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ=4.21 (d, 2H), 4.72 (s, 2H), 4.94 (d, 1H),5.09 (d, 1H), 5.63-5.76 (m, 1H), 7.31-7.43 (m, 2H), 7.71 (s, 1H).

Example 167A2-[(5-Chloro-2-thienyl)carbonyl]-N-(2-methoxyethyl)hydrazinecarboxamide

A quantity of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazidewas suspended largely finely in 30 ml of dry THF at 50° C. Then 1.81 g(17.90 mmol) of 1-isocyanato-2-methoxyethane in solution in 30 ml of THFwere added dropwise. The mixture was stirred at 50° C. for 2.5 h. Aftercooling to RT, the solvent was removed on a rotary evaporator and theresidue was admixed with diethyl ether. The crystals were filtered offwith suction, washed with diethyl ether and dried in an HV. This gave4.87 g (100% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.14-3.21 (m, 2H), 3.28-3.36 (m, 5H), 6.52(br. s., 1H), 7.22 (d, 1H), 7.70 (d, 1H), 7.97 (s, 1H), 10.24 (s, 1H).

Example 168A5-(5-Chloro-2-thienyl)-4-(2-methoxyethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Of the compound from Example 167A, 4.85 g (17.46 mmol) were dissolved in17 ml (52.39 mmol) of 3M aqueous sodium hydroxide solution and heatedunder reflux for 168 h. During this, after 16, 40, 64 and 88 h, 1.05 gportions (26.19 mmol, in total 104.76 mmol) of solid sodium hydroxidewere added. The batch was acidified to pH 10 using 1M hydrochloric acid,and the mixture was extracted with twice 30 ml of ethyl acetate. Thecombined organic phases were dried over sodium sulphate, filtered, freedfrom the solvent on a rotary evaporator and dried in an HV. This gave2.44 g (54% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.20 (s, 3H), 3.53 (t, 2H), 3.92 (t, 2H),7.24 (d, 1H), 7.51 (d, 1H), 12.04 (s, 1H).

Example 169A Ethyl[3-(5-chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate

Of the compound from Example 168A, 2.4 g (9.24 mmol) were suspended with2.55 g (18.48 mmol) of potassium carbonate in 48 ml of acetonitrile.Then 1.08 ml (10.17 mmol) of ethyl chloroacetate were added and themixture was heated under reflux at 80° C. for 4.5 h. A further 113 mg(0.92 mmol) of ethyl chloroacetate were added, with stirring at 80° C.for 2 h. The suspension was filtered through a layer of silica gel,which was washed with ethyl acetate, and the filtrate was concentratedon a rotary evaporator and dried in an HV. This gave 3.24 g (100% oftheory) of the title compound.

LC/MS [Method 6]: R_(t)=2.42 min; m/z=346 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.21 (t, 3H), 3.30 (s, 3H), 3.55 (t, 2H),3.99 (t, 2H), 4.15 (q, 2H), 4.65 (s, 2H), 7.27 (d, 1H), 7.58 (d, 1H).

Example 170A[3-(5-Chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid

Of the compound from Example 169A, 3.2 g (9.25 mmol) were dissolved in28 ml of methanol. Then 2.82 ml of 20% strength aqueous potassiumhydroxide solution were added. The mixture was stirred at RT for 2 h.The methanol fraction was reduced to half on a rotary evaporator. Themixture was then diluted with water and extracted once with 15 ml ofethyl acetate. The aqueous phase was acidified with 920 μl ofconcentrated hydrochloric acid and extracted with twice 15 ml of ethylacetate. The combined organic phases were dried over sodium sulphate,filtered and freed from the solvent on a rotary evaporator. Drying in anHV gave 2.34 g (80% of theory) of the title compound.

LC/MS [Method 6]: R_(t)=2.05 min; m/z=318 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=3.20 (s, 3H), 3.55 (t, 2H), 3.99 (t, 2H),4.53 (s, 2H), 7.27 (d, 1H), 7.58 (d, 1H), 13.14 (br. s., 1H).

Example 171A Methyl3-[(tert-butoxycarbonyl)amino]-3-(2-methoxyphenyl)propanoate

A quantity of 1.0 g (4.10 mmol) of methyl3-amino-3-(2-methoxyphenyl)propanoate was suspended in 25 ml of dioxaneand 27.5 ml of 5% strength aqueous sodium hydrogen carbonate solution.Then 0.89 g (4.10 mmol) of di-tert-butyl dicarbonate were added. Themixture was stirred at RT overnight. The white suspension was admixedwith 50 ml of water and extracted with three times 25 ml of ethylacetate. The combined organic phases were dried over magnesium sulphate,filtered and freed from the solvent on a rotary evaporator. This gave1.34 g (100% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.06 min; m/z=310 (M+H)⁺.

Example 172A tert-Butyl [3-hydroxy-1-(2-methoxyphenyl)propyl]carbamate

Of the compound from Example 171A, 1.34 g (4.33 mmol) were dissolved in10 ml of dimethoxyethane and admixed with 246 mg (6.50 mmol) of sodiumborohydride and 37 mg (0.87 mmol) of lithium chloride. The mixture washeated at 85° C. for 16 h. For work-up, it was cooled to RT andcautiously admixed with 10 ml of saturated aqueous sodium potassiumtartrate solution. It was extracted with three times 20 ml of ethylacetate. The combined organic phases were dried over magnesium sulphate,filtered and freed from the solvent on a rotary evaporator. The crudeproduct was purified by chromatography on silica gel (elution:cyclohexane/ethyl acetate 9:1, 7:3). This gave 348 mg (29% of theory) ofthe title compound.

LC/MS [Method 2]: R_(t)=1.90 min; m/z=282 (M+H)⁺.

Example 173A 3-Amino-3-(2-methoxyphenyl)propan-1-ol hydrochloride

Of the compound from Example 172A, 100 mg (0.36 mmol) were dissolved in2 ml of dichloromethane, and 1.63 ml (6.52 mmol) of a 4M solution ofhydrogen chloride in dioxane were added. The yellow solution wassubsequently stirred at RT for 1 h. The reaction mixture was evaporatedto dryness on a rotary evaporator and dried in an HV. This gave 88 mg(100% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.90-2.11 (m, 2H), 3.28-3.44 (m, 2H), 3.83(s, 3H), 4.52-4.61 (m, 1H), 4.76 (br. s., 1H), 7.02 (t, 1H), 7.09 (d,1H), 7.40 (t, 2H), 8.21 (br. s., 3H).

Example 174A 3-Amino-3-(2-methoxyphenyl)propyl carbamate hydrochloride

Of the compound from Example 172A, 242 mg (0.86 mmol) were introduced in12 ml of acetonitrile under argon, and admixed dropwise at −15° C. with105 μl (1.20 mmol) of chlorosulphonyl isocyanate. The reaction mixturewas stirred at −10° C. for 30 minutes. Then 12 ml of water were addedand the mixture was stirred at 60° C. overnight. The reaction mixturewas cooled, rendered basic using saturated aqueous sodium hydrogencarbonate solution and extracted with three times 10 ml of ethylacetate. The organic phases were combined, dried over magnesiumsulphate, filtered and freed from the solvent on a rotary evaporator.The residue was admixed with 6 ml of a 4M solution of hydrogen chloridein dioxane, the components were stirred together for 10 minutes, and themixture was concentrated on a rotary evaporator. The residue was driedin an HV. This gave 186 mg (83% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=2.03-2.29 (m, 2H), 3.64-3.76 (m, 2H), 3.83(s, 3H), 4.49-4.61 (m, 1H), 6.98-7.13 (m, 2H), 7.34-7.46 (m, 2H), 8.23(br. s., 1H), 8.35 (br. s., 2H).

Example 175A 2-Amino-2-(2,3-dichlorophenyl)ethanol

Quantities of 1.0 g (4.54 mmol) of amino-(2,3-dichlorophenyl)acetic acidand 18.18 ml (18.18 mmol) of borane-THF complex (1M solution in THF)were stirred together at RT until the reaction was complete. Forwork-up, pieces of ice were added. After the end of the evolution ofgas, the mixture was adjusted to a pH of 9-10 using 1M aqueous sodiumhydroxide solution, and extracted three times with tert-butyl methylether. The combined organic phases were dried over sodium sulphate,filtered and freed from the solvent on a rotary evaporator. Drying in anHV gave 880 mg (91% of theory) of the title compound.

LC/MS [Method 5]: R_(t)=0.39 min; m/z=206 and 208 (M+H)⁺.

Example 176A Methyl[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate

Of the compound from Example 76A, 1.2 g (3.32 mmol), 150 mg of platinumon carbon (5%) and 150 ml of methanol were hydrogenated under standardhydrogen pressure. For work-up, the catalyst was filtered off and thefiltrate was concentrated on a rotary evaporator. The crude product waspurified by preparative HPLC (Method 20). The product fractions werecombined and freed from the solvent on a rotary evaporator. Drying in anHV gave 890 mg (73% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=1.00 min; m/z=364 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=2.55-2.68 (m, 2H), 3.69 (s, 3H), 4.01 (t,2H), 4.70 (s, 2H), 7.61-7.72 (m, 4H).

Example 177A[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid

Of the compound from Example 176A, 1.27 g (3.49 mmol), were introducedin 200 ml of methanol and 100 ml of water. Then 6.98 ml (6.98 mmol) of1M aqueous lithium hydroxide solution were added. The mixture wasstirred at RT for 2 h. For purification, 15 ml of 1N hydrochloric acidwere added and the mixture was freed from methanol on a rotaryevaporator. The residue was diluted with 100 ml of water and extractedthree times with ethyl acetate. The combined organic phases were driedover sodium sulphate, filtered and freed from the solvent on a rotaryevaporator, and dried in an HV. This gave 1.11 g (91% of theory) of thetitle compound.

LC/MS [Method 2]: R_(t)=1.92 min; m/z=350 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=2.55-2.68 (m, 2H), 4.01 (t, 2H), 4.56 (s,2H), 7.61-7.72 (m, 4H), 13.12 (br. s., 1H).

Example 178A tert-Butyl{2-hydroxy-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate (enantiomer I)

Of the compound from Example 62A, 52.8 g were separated by chiralpreparative HPLC [Method 33]. The first-eluting enantiomer (21 g) wasobtained with 93% ee according to chiral analytical HPLC (Method 34).

Chiral analytical HPLC [Method 34]: R_(t)=1.74 min

For the last-eluting enantiomer, see Example 179A.

Example 179A tert-Butyl{2-hydroxy-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate (enantiomer II)

Last-eluting enantiomer (18.9 g, 99.7% ee) from the separation of 52.8 gof the compound from Example 62A, by Method 33.

Chiral analytical HPLC [Method 34]: R_(t)=2.48 min.

LC/MS [Method 3]: R_(t)=1.13 min; m/z=206 (M-BOC)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.35 (s, 9H), 3.36-3.50 (m, 2H), 4.90-5.01(m, 2H), 7.37-7.48 (m, 2H), 7.61-7.70 (m, 4H).

Further separation of the mixed fraction under the same conditions gavea further 4.0 g of the second enantiomer with 99.5% ee.

Example 180A 2-Amino-2-[2-(trifluoromethyl)phenyl]ethyl carbamatehydrochloride (enantiomer II)

Of the compound from Example 179A, 250 mg (0.82 mmol) were introduced in9.76 ml of acetonitrile under argon. At −15° C., 100 μl (1.15 mmol) ofchlorosulphonyl isocyanate were added dropwise. After 30 min, thereaction solution was admixed with 20 ml of water and heated at 60° C.overnight. The batch was cooled and introduced into saturated aqueoussodium hydrogen carbonate solution. It was extracted twice with ethylacetate. The combined organic phases were dried over sodium sulphate,filtered and freed from the solvent on a rotary evaporator. Drying in anHV gave 220 mg (100% of theory) of the title compound.

LC/MS [Method 4]: R_(t)=0.39 min; m/z=249 (M+H)⁺.

Example 181A [(tert-Butoxycarbonyl)amino](2,3-dichlorophenyl)acetic acid

A quantity of 500 mg (2.27 mmol) of amino(2,3-dichlorophenyl)acetic acidwas suspended in 5 ml of dioxane and 5% strength aqueous sodium hydrogencarbonate solution. Then 522 μl (2.27 mmol) of di-tert-butyl dicarbonatewere added. The batch was stirred at RT overnight. The reaction mixturewas extracted twice with ethyl acetate. The aqueous phase was acidifiedwith 1M hydrochloric acid and extracted twice with ethyl acetate. Thecombined organic phases were dried over sodium sulphate, filtered andfreed from the solvent on a rotary evaporator. Drying in an HV gave 703mg (94% of theory) of the title compound.

LC/MS [Method 5]: R_(t)=1.02 min; m/z=318 and 320 (M−H)⁻.

Example 182A tert-Butyl [1-(2,3-dichlorophenyl)-2-hydroxyethyl]carbamate

Of the compound from Example 181A, 702 mg (2.19 mmol) were dissolved in7 ml of THF under argon and cooled to 0° C. Then 306 μl (2.19 mmol) oftriethylamine and 313 μl (2.41 mmol) of isobutyl chloroformate wereadded dropwise. The suspension was stirred at 0° C. for 1 h. It wasfiltered through a Seitz frit into a cooled flask, with washing with alittle THF. The resulting filtrate was added slowly dropwise to asolution, cooled to 0° C., of 249 mg (6.58 mmol) of sodium borohydridein 1.5 ml of water. After 1 h, the batch was cautiously admixed withsaturated aqueous sodium hydrogen carbonate solution and extracted withethyl acetate. The organic phase was also washed once with saturatedaqueous sodium hydrogen carbonate solution and once with saturatedaqueous sodium chloride solution. It was dried over sodium sulphate,filtered and freed from the solvent on a rotary evaporator. Drying in anHV gave 537 mg (56% of theory) of the title compound in 70% purity.

LC/MS [Method 4]: R_(t)=1.02 min; m/z=306 and 308 (M+H)⁺.

Example 183A 2-Amino-2-(2,3-dichlorophenyl)ethyl carbamate

Of the compound from Example 182A, 290 mg (about 0.95 mmol) wereintroduced in 5 ml of acetonitrile under argon. At −15° C., 115 μl (1.33mmol) of chlorosulphonyl isocyanate were added dropwise. After 30 min,the reaction solution was admixed with 20 ml of water and heated at 60°C. overnight. The reaction mixture was cooled and introduced intosaturated aqueous sodium hydrogen carbonate solution. It was extractedwith twice 20 ml of ethyl acetate. The combined organic phases weredried over sodium sulphate, filtered and freed from the solvent on arotary evaporator. Drying in an HV gave 176 mg (66% of theory) of thetitle compound in 89% purity.

LC/MS [Method 2]: R_(t)=1.07 min; m/z=249 (M+H)⁺.

Example 184A 2-Amino-2-[3-(trifluoromethyl)phenyl]ethyl carbamate

Of the compound from Example 59A, 93 mg (0.31 mmol) were introduced in 4ml of acetonitrile under argon. At −15° C., 37 μl (0.43 mmol) ofchlorosulphonyl isocyanate were added dropwise. After 30 min, thereaction solution was admixed with 8 ml of water and heated at 60° C.overnight. The reaction mixture was cooled and introduced into saturatedsodium hydrogen carbonate solution. It was extracted with twice 10 ml ofethyl acetate. The combined organic phases were dried over sodiumsulphate, filtered and freed from the solvent on a rotary evaporator.Drying in an HV gave 66 mg (64% of theory) of the title compound in 73%purity.

LC/MS [Method 3]: R_(t)=0.50 min; m/z=249 (M+H)⁺.

Example 185A[4-(4-Chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]aceticacid (enantiomer mixture)

A quantity of 1.0 g (3.75 mmol) of methyl[4-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]acetate (preparedaccording to WO 2007/134862 Example 323A) was dissolved with 796 mg(4.13 mmol) of 3-bromo-1,1,1-trifluoropropan-2-ol in 50 ml of acetone,1.47 g (4.50 mmol) of caesium carbonate were added at RT, and themixture was heated under reflux for 16 h. For work-up, it was cooled toRT and admixed with 50 ml of water. It was neutralised by addition of 1Mhydrochloric acid and extracted with three times 50 ml of ethyl acetate.The combined organic phases were dried over sodium sulphate, filteredand concentrated under reduced pressure. The crude product was purifiedby preparative HPLC [Method 19]. This gave 171 mg (13% of theory) of thetarget compound.

LC-MS [Method 3] R_(t)=1.02 min; MS [ESIpos]: m/z=365 (M+H)⁺

Example 186A2-[(tert-Butoxycarbonyl)amino]-2-[2-(trifluoromethyl)phenyl]ethylethylcarbamate (enantiomerically pure)

A quantity of 379 μl (4.78 mmol) of ethyl isocyanate was added to asolution of 365 mg (1.20 mmol) of the compound from Example 179A and 15mg (0.12 mmol) of 4-dimethylaminopyridine in 7 ml of pyridine. Thereaction mixture was stirred at 50° C. overnight. After cooling to RT,the mixture was admixed with 0.5 ml of ammonia solution (35% in water).The volatile constituents were removed on a rotary evaporator. Theresidue was dissolved in a little acetonitrile and 1N hydrochloric acid,and separated by preparative HPLC [Method 20]. The product-containingfraction was freed from the solvents on a rotary evaporator and theresidue was dried in an HV. This gave 380 mg (84% of theory) of thetitle compound.

LC-MS [Method 4] R_(t)=1.09 min; MS [ESIpos]: m/z=377 (M+H)⁺

Example 187A 2-Amino-2-[2-(trifluoromethyl)phenyl]ethyl ethylcarbamatehydrochloride (enantiomerically pure)

Of the compound from Example 186A, 345 mg (0.92 mmol) were admixed with10 ml of a 4N solution of hydrogen chloride in dioxane, and the mixturewas stirred at RT for 30 min All volatile constituents were then removedon a rotary evaporator. The residue (311 mg, 100% of theory) was thetitle compound.

LC-MS [Method 2] R_(t)=1.20 min; MS [ESIpos]: m/z=277 (M+H)⁺

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=1.00 (t, 3H), 2.93-3.06 (m, 2H), 4.28(dd, 1H), 4.38 (dd, 1H), 4.62-4.70 (m, 1H), 7.12 (br. t, 1H), 7.67 (t,1H), 7.80-7.88 (m, 2H), 7.98 (d, 1H), 8.84 (br. s., 3H).

Implementing Examples Example 12-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-nitro-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 337 mg (0.92 mmol) were introducedtogether with 274 mg (1.01 mmol, 1.1 eq.) of the compound from Example13A, 247 mg (1.29 mmol, 1.4 eq.) of EDC and 174 mg (1.29 mmol, 1.4 eq.)of HOBt with 8 ml of DMF, and then 192 μl (1.10 mmol, 1.2 eq.) ofN,N-diisopropylethylamine were added. The mixture was stirred at RT for1 h, then purified by preparative HPLC (Method 10). This gave 445 mg(81% of theory) of the title compound.

LC-MS [Method 2]: R_(t)=2.46 min; MS [ESIpos]: m/z=582 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=9.07 (d, 1H), 7.83 (s, 1H), 7.66-7.79 (m,4H), 7.56-7.66 (m, 3H), 6.925 (d, 0.5H (1H from diastereomer I)), 6.91(d, 0.5H (1H from diastereomer II)), 5.63-5.77 (m, 1H), 5.08 (dd, 1H),4.95 (dd, 1H), 4.53 (s, 1H (2H from diastereomer I)), 4.43-4.61 (m [AB],1H (2H from diastereomer II)), 4.18-4.37 (m, 1H), 3.96 (br. d, 1H), 3.83(dd, J=14.7, 9.5 Hz, 1H).

The diastereomers from Example 1 were separated by preparativechromatography on a chiral phase (Method 11a): see Example 2 and Example3.

Example 22-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-nitro-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer from the separation of Example 1 by Method11a.

LC-MS [Method 2]: R_(t)=2.43 min; MS [ESIpos]: m/z=582 (M+H)⁺

Analytical chiral HPLC [Method 12a]: R_(t)=4.40 min

Example 32-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-nitro-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer from the separation of Example 1 by Method11a.

LC-MS [Method 2]: R_(t)=2.44 min; MS [ESIpos]: m/z=582 (M+H)⁺

Analytical chiral HPLC [Method 12a]: R_(t)=5.37 min.

Example 42-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-nitro-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

In the same way as for the preparation of Example 1, from 766 mg (2.09mmol) of the compound from Example 8A and 656 mg (2.30 mmol) of thecompound from Example 17A, 880 mg (72% of theory) of the title compoundwere obtained.

LC-MS [Method 5]: R_(t)=1.12 min; MS [ESIpos]: m/z=582 (M+H)⁺

The diastereomers from Example 4 were separated by preparativechromatography on a chiral phase (Method 11b): see Example 5 and Example6.

Example 52-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-nitro-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer (419 mg) from the diastereomer separation of880 mg of the compound from Example 4 by Method 11b.

LC-MS [Method 2]: R_(t)=2.40 min; MS [ESIpos]: m/z=582 (M+H)⁺

Analytical chiral HPLC [Method 12a]: R_(t)=4.20 min.

¹H NMR (DMSO-d₆, 400 MHz): δ=9.20 (d, 1H), 7.82 (d, 1H), 7.80-7.71 (m,4H), 7.63 (d, 2H), 7.58 (t, 1H), 6.92 (d, 1H), 6.02-5.94 (m, 1H), 4.92(dd, 1H), 4.82 (dd, 1H), 4.49 (s, 2H), 4.32-4.19 (m, 1H), 3.95 (dd, 1H),3.82 (dd, 1H).

Example 62-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-nitro-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer (417 mg) from the diastereomer separation of880 mg of the compound from Example 4 by Method 11b.

LC-MS [Method 2]: R_(t)=2.39 min; MS [ESIpos]: m/z=582 (M+H)⁺

Analytical chiral HPLC [Method 12a]: R_(t)=5.64 min.

¹H NMR (DMSO-d₆, 400 MHz): δ=9.20 (d, 1H), 7.82 (d, 1H), 7.80-7.70 (m,4H), 7.62 (d, 2H), 7.58 (t, 1H), 6.90 (d, 1H), 6.00-5.93 (m, 1H), 4.92(dd, 1H), 4.82 (dd, 1H), 4.48 (dd [AB], 2H), 4.31-4.20 (m, 1H), 3.96(dd, 1H), 3.82 (dd, 1H).

Example 72-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-[2,3-dichlorophenyl]-2-nitroethyl}acetamide(diastereomer mixture)

In the same way as for the preparation of Example 1, from 422 mg (1.16mmol) of the compound from Example 8A and 363 mg (1.27 mmol) of thecompound from Example 21A, 638 mg (91% of theory) of the title compoundwere obtained.

LC-MS [Method 5]: R_(t)=1.13 min; MS [ESIpos]: m/z=582 (M+H)⁺

The diastereomers from Example 7 were separated by preparativechromatography on a chiral phase (Method 11c): see Example 8 and Example9.

Example 82-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-[2,3-dichlorophenyl]-2-nitroethyl}acetamide(diastereomer I)

First-eluting diastereomer (181 mg) from the diastereomer separation of630 mg of the compound from Example 7 by Method 11c.

LC-MS [Method 2]: R_(t)=2.44 min; MS [ESIpos]: m/z=582 (M+H)⁺

Analytical chiral HPLC [Method 12b]: R_(t)=5.81 min.

¹H NMR (DMSO-d₆, 400 MHz): δ=9.22 (d, 1H), 7.74 (d, 2H), 7.67-7.61 (m,3H), 7.55 (dd, 1H), 7.43 (t, 1H), 6.91 (d, 1H), 6.04-5.97 (m, 1H), 5.01(dd, 1H), 4.81 (dd, 1H), 4.58-4.47 (m[AB], 2H), 4.33-4.21 (m, 1H), 3.95(dd, 1H), 3.82 (dd, 1H).

Example 92-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-[2,3-dichlorophenyl]-2-nitroethyl}acetamide(diastereomer II)

Last-eluting diastereomer (281 mg) from the diastereomer separation of630 mg of the compound from Example 7 by Method 11c.

LC-MS [Method 2]: R_(t)=2.44 min; MS [ESIpos]: m/z=582 (M+H)⁺

Analytical chiral HPLC [Method 12b]: R_(t)=6.66 min.

¹H NMR (DMSO-d₆, 400 MHz): δ=9.22 (d, 1H), 7.74 (d, 2H), 7.66 (d, 1H),7.63 (d, 2H), 7.55 (dd, 1H), 7.44 (t, 1H), 6.90 (d, 1H), 6.04-5.96 (m,1H), 5.01 (dd, 1H), 4.81 (dd, 1H), 4.58-4.47 (m[AB], 2H), 4.31-4.20 (m,1H), 3.96 (dd, 1H), 3.82 (dd, 1H).

Example 10N-{2-Amino-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamidehydrochloride (diastereomer mixture)

Of the compound from Example 1, 45 mg (77 μmol) and 40 mg (348 μmol) ofindium powder were admixed in 0.5 ml of THF with 42 μl of conc.hydrochloric acid, and the mixture was stirred at RT for 2 h. Then themixture was purified by preparative HPLC (Method 10). Theproduct-containing fractions were admixed with 2 ml of 1N hydrochloricacid and concentrated on a rotary evaporator. Drying in an HV gave 21 mg(46% of theory) of the title compound as a diastereomer mixture.

LC-MS [Method 5]: R_(t)=0.85 min; MS [ESIpos]: m/z=552 (M+H)⁺

Example 11N-{2-Amino-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamidehydrochloride (diastereomer I)

In a continuous-flow hydrogenation apparatus (H-Cube from Thales Nano,Budapest, Model HC-2-SS) a solution of 325 mg (0.56 mmol) of thecompound from Example 2 in 50 ml of methanol was hydrogenated(conditions: Raney Nickel cartridge, flow rate of 1 ml/min, 45° C.,standard hydrogen pressure). The methanol was removed on a rotaryevaporator and the residue was purified by preparative HPLC (Method 10).The product-containing fractions were admixed with 20 ml of 1Nhydrochloric acid and concentrated on a rotary evaporator. Drying in anHV gave 266 mg (81% of theory) of the title compound.

LC-MS [Method 4]: R_(t)=0.90 min; MS [ESIpos]: m/z=552 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.99 (d, 1H), 7.99-8.21 (m, 3H), 7.67-7.80(m, 5H), 7.57-7.67 (m, 3H), 6.89 (d, 1H), 5.18-5.28 (m, 1H), 4.50-4.67(m [AB], 2H), 4.21-4.34 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.13-3.28(m, 2H).

Example 12N-{2-Amino-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamidehydrochloride (diastereomer II)

In the same way as for Example 11, but at RT, 316 mg (0.54 mmol) of thecompound from Example 3 were hydrogenated. This gave 180 mg (56% oftheory) of the title compound.

LC-MS [Method 4]: R_(t)=0.89 min; MS [ESIpos]: m/z=552 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=9.00 (d, 1H), 8.12 (br.s, 3H), 7.66-7.81(m, 5H), 7.57-7.66 (m, 3H), 6.94 (d, 1H), 5.20-5.29 (m, 1H), 4.50-4.66(m [AB], 2H), 4.20-4.33 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.13-3.28(m, 2H).

Example 13N-{2-Amino-1-[2-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamidehydrochloride (diastereomer I)

In the same way as for Example 11, but at RT, 415 mg (0.71 mmol) of thecompound from Example 5 in 100 ml of methanol were hydrogenated. Thisgave 330 mg (79% of theory) of the title compound.

LC-MS [Method 6]: R_(t)=1.57 min; MS [ESIpos]: m/z=552 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=9.11-9.18 (m, 1H), 8.24 (br.s, 3H), 7.87(d, 1H), 7.71-7.78 (m, 4H), 7.60-7.65 (m, 2H), 7.55 (t, 1H), 6.93 (d,1H), 5.44-5.53 (m, 1H), 4.66 (dd, 1H), 4.52 (d, 1H), 4.19-4.30 (m, 1H),3.96 (dd, 1H), 3.82 (dd, 1H), 3.07-3.22 (m, 1H), 2.95-3.07 (m, 1H).

Example 14N-{2-Amino-1-[2-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamidehydrochloride (diastereomer II)

In the same way as for Example 11, but at RT, 415 mg (0.71 mmol) of thecompound from Example 6 in 100 ml of methanol were hydrogenated. Thisgave 330 mg (79% of theory) of the title compound.

LC-MS [Method 6]: R_(t)=1.56 min; MS [ESIpos]: m/z=552 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=9.08-9.17 (m, 1H), 8.21 (br.s, 3H), 7.86(d, 1H), 7.70-7.78 (m, 4H), 7.62 (d, 2H), 7.53-7.59 (m, 1H), 6.88 (d,1H), 5.44-5.52 (m, 1H), 4.67 (d, 1H), 4.51 (d, 1H), 4.20-4.32 (m, 1H),3.96 (dd, 1H), 3.82 (dd, 1H), 3.09-3.22 (m, 1H), 2.96-3.08 (m, 1H).

Example 15N-[2-Amino-1-(2,3-dichlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamidehydrochloride (diastereomer I)

In the same way as for Example 11, but at RT, 180 mg (0.31 mmol) of thecompound from Example 8 in 50 ml of methanol were hydrogenated. Thisgave 116 mg (64% of theory) of the title compound.

LC-MS [Method 6]: R_(t)=1.61 min; MS [ESIpos]: m/z=552 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=9.15 (d, 1H), 8.23 (br.s, 3H), 7.75 (d,2H), 7.57-7.66 (m, 4H), 7.42 (t, 1H), 6.93 (d, 1H), 5.53 (td, 1H),4.52-4.68 (m, 2H), 4.19-4.31 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H),3.06-3.18 (m, 2H).

Example 16N-[2-Amino-1-(2,3-dichlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamidehydrochloride (diastereomer II)

In the same way as for Example 11, but at RT, 280 mg (0.48 mmol) of thecompound from Example 9 in 80 ml of methanol were hydrogenated. Thisgave 177 mg (63% of theory) of the title compound.

LC-MS [Method 5]: R_(t)=0.84 min; MS [ESIpos]: m/z=552 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=9.23 (d, 1H), 8.26 (br.s, 3H), 7.74 (d,2H), 7.58-7.67 (m, 4H), 7.42 (t, 1H), 6.90 (d, 1H), 5.52 (q, 1H),4.52-4.69 (m [AB], 2H), 4.22-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H),3.08-3.18 (m, 2H).

Example 172-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(formylamino)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Using the method described in Example 1, from 62 mg (0.17 mmol) of thecompound from Example 8A and 50 mg (0.19 mmol) of the compound fromExample 24A, the title compound was obtained: 80 mg (82% of theory).

LC-MS [Method 5]: R_(t)=1.06 min; MS [ESIpos]: m/z=580 (M+H)⁺

The diastereomers from Example 17 were separated by preparativechromatography on a chiral phase (Method 17a): see Example 18 andExample 19.

Example 182-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(formylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer (28 mg) from the separation of 80 mg of thecompound from Example 17 by Method 17a.

LC-MS [Method 4]: R_(t)=1.04 min; MS [ESIpos]: m/z=580 (M+H)⁺

Analytical chiral HPLC [Method 18a]: R_(t)=5.28 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.72 (d, 1H), 8.17 (t, 1H), 7.99 (s, 1H),7.75 (d, 2H), 7.69 (s, 1H), 7.55-7.68 (m, 5H), 6.92 (d, 1H), 5.00-5.08(m, 1H), 4.51 (s, 2H), 4.21-4.35 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H),3.46-3.55 (m, 1H), 3.32-3.40 (m, 1H).

Example 192-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(formylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer (30 mg) from the separation of 80 mg of thecompound from Example 17 by Method 17a.

LC-MS [Method 4]: R_(t)=1.04 min; MS [ESIpos]: m/z=580 (M+H)⁺

Analytical chiral HPLC [Method 18a]: R_(t)=15.29 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.73 (d, 1H), 8.16 (t, 1H), 7.99 (s, 1H),7.74 (d, 2H), 7.69 (s, 1H), 7.56-7.67 (m, 5H), 6.89 (d, 1H), 5.00-5.08(m, 1H), 4.45-4.56 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.97 (dd, 1H), 3.83(dd, 1H), 3.47-3.55 (m, 1H), 3.32-3.40 (m, 1H).

Example 20N-{2-(Acetylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Using the method described in Example 1, from 82 mg (0.22 mmol) of thecompound from Example 8A and 70 mg (0.25 mmol) of the compound fromExample 26A, the title compound was obtained: 110 mg (75% of theory).

LC-MS [Method 2] R_(t)=2.26/2.28 min; MS [ESIpos]: m/z=594 (M+H)⁺

The two diastereomers were separated by preparative chromatography on achiral phase (Method 17e): see Examples 21 and 22.

Example 21N-{2-(Acetylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

First-eluting diastereomer (42 mg) from the separation of 110 mg of thecompound from Example 20 by Method 17e.

LC-MS [Method 4]: R_(t)=1.06 min; MS [ESIpos]: m/z=594 (M+H)⁺

Analytical chiral HPLC [Method 18a]: R_(t)=4.18 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.67 (d, 1H), 8.01 (t, 1H), 7.76 (d, 2H),7.54-7.68 (m, 6H), 6.94 (d, 1H), 4.96-5.04 (m, 1H), 4.45-4.56 (m [AB],2H), 4.25-4.36 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.36-3.46 (m, 1H),3.27-3.35 (m, 1H), 1.75 (s, 3H).

Example 22N-{2-(Acetylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

Last-eluting diastereomer (43 mg) from the separation of 110 mg of thecompound from Example 20 by Method 17e.

LC-MS [Method 4]: R_(t)=1.08 min; MS [ESIpos]: m/z=594 (M+H)⁺

Analytical chiral HPLC [Method 18a]: R_(t)=9.35 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.68 (d, 1H), 8.01 (t, 1H), 7.75 (d, 2H),7.55-7.68 (m, 6H), 6.92 (d, 1H), 4.96-5.03 (m, 1H), 4.45-4.55 (m, 2H),4.24-4.36 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.37-3.45 (m, 1H),3.26-3.36 (m, 1H), 1.75 (s, 3H).

Example 232-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(methylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

A mixture of 52 mg of the compound from Example 8A (0.14 mmol) and 27 mg(0.20 mmol) of HOBt in 2 ml of DMF was introduced, admixed with 38 mg(0.20 mmol) of EDC and stirred at RT for 20 min. Then 50 mg (0.16 mmol)of the compound from Example 50A and 35 μl (0.20 mmol) ofN,N-diisopropylethylamine were added and the reaction mixture wasstirred further at RT overnight. The entire mixture was purifiedcompletely by preparative HPLC (Method 10). This gave 68 mg (76% oftheory) of the title compound.

LC-MS [Method 2]: R_(t)=2.32 min; MS [ESIpos]: m/z=630 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.70 (d, 1H), 7.71-7.78 (m, 3H), 7.57-7.70(m, 5H), 7.24 (t, 1H), 6.92 (d, 1H), 5.02-5.11 (m, 1H), 4.48-4.60 (m[AB], 2H), 4.23-4.34 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.25-3.33(m, 2H), 2.86 (s, 3H).

Example 242-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(methylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

A mixture of 45 mg of the compound from Example 8A (0.12 mmol) and 23 mg(0.17 mmol, 1.4 eq.) of HOBt in 1.7 ml of DMF was introduced, admixedwith 33 mg (0.17 mmol, 1.4 eq.) of EDC and stirred at RT for 20 min.Then 43 mg (0.14 mmol, 1.1 eq.) of the compound from Example 47A and 30μl (0.17 mmol, 1.4 eq.) of N,N-diisopropylethylamine were added and thereaction mixture was stirred further at RT overnight. The entire mixturewas purified by preparative HPLC (Method 10). This gave 51 mg (66% oftheory) of the title compound.

LC-MS [Method 2]: R_(t)=2.30 min; MS [ESIpos]: m/z=630 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.72 (d, 1H), 7.72-7.77 (m, 3H), 7.57-7.70(m, 5H), 7.24 (t, 1H), 6.89 (d, 1H), 5.02-5.10 (m, 1H), 4.46-4.62 (m[AB], 2H), 4.22-4.32 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.25-3.31(m, 2H), 2.86 (s, 3H).

Example 252-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(methylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

In the same way as for Example 24, from 54 mg (0.15 mmol) of thecompound from Example 8A and 52 mg (0.16 mmol) of the compound fromExample 53A, the title compound was obtained: 73 mg (78% of theory).

LC-MS [Method 5]: R_(t)=1.07 min; MS [ESIpos]: m/z=630 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.75 (d, 1H), 7.68-7.80 (m, 5H), 7.62 (d,2H), 7.51 (t, 1H), 7.41 (t, 1H), 6.93 (d, 1H), 5.30-5.38 (m, 1H), 4.61(d, 1H), 4.47 (d, 1H), 4.22-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H),3.12-3.27 (m, 2H), 2.88 (s, 3H).

Example 262-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(methylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

In the same way as for Example 24, from 57 mg (0.16 mmol) of thecompound from Example 8A and 55 mg (0.17 mmol) of the compound fromExample 54A, the title compound was obtained: 70 mg (71% of theory).

LC-MS [Method 5]: R_(t)=1.06 min; MS [ESIpos]: m/z=630 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.76 (d, 1H), 7.70-7.80 (m, 5H), 7.61 (d,2H), 7.52 (t, 1H), 7.41 (t, 1H), 6.89 (d, 1H), 5.29-5.37 (m, 1H), 4.62(d, 1H), 4.46 (d, 1H), 4.21-4.34 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H),3.13-3.27 (m, 2H), 2.88 (s, 3H).

Example 272-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-(2,3-dichlorophenyl)-2-[(methylsulphonyl)amino]ethyl}acetamide(diastereomer I)

In the same way as for Example 24, from 50 mg (0.14 mmol) of thecompound from Example 8A and 48 mg (0.15 mmol) of the compound fromExample 57A, the title compound was obtained: 64 mg (74% of theory).

LC-MS [Method 5]: R_(t)=1.08 min; MS [ESIpos]: m/z=630 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.76 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.59 (dd, 1H), 7.51 (dd, 1H), 7.40 (t, 1H), 7.36 (t, 1H), 6.92 (d, 1H),5.37 (td, 1H), 4.49-4.62 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.96 (dd, 1H),3.82 (dd, 1H), 3.25-3.33 (m, 1H), 3.17 (ddd, 1H), 2.90 (s, 3H).

Example 282-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-(2,3-dichlorophenyl)-2-[(methylsulphonyl)amino]ethyl}acetamide(diastereomer II)

In the same way as for Example 24, from 51 mg (0.14 mmol) of thecompound from Example 8A and 49 mg (0.15 mmol) of the compound fromExample 58A, the title compound was obtained: 59 mg (67% of theory).

LC-MS [Method 5]: R_(t)=1.08 min; MS [ESIpos]: m/z=630 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.77 (d, 1H), 7.74 (d, 2H), 7.58-7.64 (m,3H), 7.51 (br.d, 1H), 7.42 (t, 1H), 7.36 (t, 1H), 6.89 (d, 1H), 5.37(td, 1H), 4.46-4.64 (m [AB], 2H), 4.21-4.31 (m, 1H), 3.96 (dd, 1H), 3.82(dd, 1H), 3.25-3.35 (m, 1H), 3.17 (ddd, 1H), 2.89 (s, 3H).

Example 292-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(ethylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

In the same way as for Example 24, from 40 mg (0.11 mmol) of thecompound from Example 8A and 40 mg (0.12 mmol) of the compound fromExample 48A, the title compound was obtained: 57 mg (81% of theory).

LC-MS [Method 5]: R_(t)=1.11 min; MS [ESIpos]: m/z=644 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.68 (d, 1H), 7.71-7.78 (m, 3H), 7.57-7.69(m, 5H), 7.27 (t, 1H), 6.93 (d, 1H), 5.00-5.08 (m, 1H), 4.48-4.58 (m[AB], 2H), 4.23-4.34 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.27 (t,2H), 2.94 (dd, 2H), 1.11 (t, 3H).

Example 302-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(ethylsulphonyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

In the same way as for Example 24, from 40 mg (0.11 mmol) of thecompound from Example 8A and 40 mg (0.12 mmol) of the compound fromExample 49A, the title compound was obtained: 56 mg (80% of theory).

LC-MS [Method 2]: R_(t)=2.35 min; MS [ESIpos]: m/z=644 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.69 (d, 1H), 7.71-7.76 (m, 3H), 7.57-7.69(m, 5H), 7.26 (t, 1H), 6.89 (d, 1H), 5.00-5.07 (m, 1H), 4.46-4.61 (m[AB], 2H), 4.21-4.33 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.27 (t,2H), 2.90-2.98 (m, 2H), 1.10 (t, 3H).

Example 312-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(ethylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

In the same way as for Example 24, from 40 mg (0.11 mmol) of thecompound from Example 8A and 40 mg (0.12 mmol) of the compound fromExample 51A, the title compound was obtained: 53 mg (75% of theory).

LC-MS [Method 5]: R_(t)=1.10 min; MS [ESIpos]: m/z=644 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.74 (d, 1H), 7.68-7.79 (m, 5H), 7.62 (d,2H), 7.51 (t, 1H), 7.46 (t, 1H), 6.93 (d, 1H), 5.27-5.35 (m, 1H),4.43-4.63 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H),3.10-3.26 (m, 2H), 2.91-3.02 (m, 2H), 1.16 (t, 3H).

Example 322-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(ethylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

In the same way as for Example 24, from 40 mg (0.11 mmol) of thecompound from Example 8A and 40 mg (0.12 mmol) of the compound fromExample 52A, the title compound was obtained: 51 mg (72% of theory).

LC-MS [Method 2]: R_(t)=2.31 min; MS [ESIpos]: m/z=644 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.74 (d, 1H), 7.69-7.79 (m, 5H), 7.61 (d,2H), 7.51 (t, 1H), 7.45 (t, 1H), 6.89 (d, 1H), 5.26-5.36 (m, 1H),4.42-4.65 (m [AB], 2H), 4.20-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H),3.10-3.25 (m, 2H), 2.90-3.02 (m, 2H), 1.15 (t, 3H).

Example 332-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-(2,3-dichlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}acetamide(diastereomer I)

In the same way as for Example 24, from 40 mg (0.11 mmol) of thecompound from Example 8A and 40 mg (0.12 mmol) of the compound fromExample 55A, the title compound was obtained: 54 mg (77% of theory).

LC-MS [Method 2]: R_(t)=2.35 min; MS [ESIpos]: m/z=644 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.72 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H),7.59 (dd, 1H), 7.50 (d, 1H), 7.36-7.43 (m, 2H), 6.92 (d, 1H), 5.31-5.39(m, 1H), 4.49-4.61 (m [AB], 2H), 4.23-4.33 (m, 1H), 3.95 (dd, 1H), 3.82(dd, 1H), 3.23-3.29 (m, 1H), 3.11-3.20 (m, 1H), 2.92-3.03 (m, 2H), 1.15(t, 3H).

Example 342-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-(2,3-dichlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}acetamide(diastereomer II)

In the same way as for Example 24, from 40 mg (0.11 mmol) of thecompound from Example 8A and 40 mg (0.12 mmol) of the compound fromExample 56A, the title compound was obtained: 56 mg (80% of theory).

LC-MS [Method 2]: R_(t)=2.34 min; MS [ESIpos]: m/z=644 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.74 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.60 (dd, 1H), 7.50 (d, 1H), 7.37-7.43 (m, 2H), 6.89 (d, 1H), 5.34 (td,1H), 4.46-4.63 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd,1H), 3.23-3.30 (m, 1H), 3.11-3.21 (m, 1H), 2.92-3.03 (m, 2H), 1.15 (t,3H).

Example 352-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

The compound from Example 59A (300 mg, 0.98 mmol) was deprotected bystirring with a 4N solution of hydrogen chloride in dioxane for 10 min,followed by removal of the volatile components on a rotary evaporatorand drying in an HV. The residue thus obtained was dissolved in 3 ml ofDMF and admixed with 202 μl (1.16 mmol) of N,N-diisopropylethylamine. Ina separate flask, 327 mg of the compound from Example 8A (0.89 mmol)were stirred with 257 mg (1.34 mmol) of EDC and 181 mg (1.34 mmol) ofHOBt in 4.8 ml of DMF at RT for 20 min. This solution was added to thesolution of the amino alcohol, and the mixture was left to react at RTfor 20 min. Then 1 ml of 1N hydrochloric acid was added and the completereaction mixture was purified by preparative HPLC (Method 10). This gave324 mg (66% of theory) of the title compound.

LC-MS [Method 5]: R_(t)=1.07 min; MS [ESIpos]: m/z=553 (M+H)⁺

The two diastereomers were separated by preparative chromatography on achiral phase (Method 17b): see Examples 36 and 37.

Example 362-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer (147 mg) from the separation of 315 mg of thecompound from Example 35 by Method 17b.

Analytical chiral HPLC [Method 18a]: R_(t)=9.82 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.71 (d, 1H), 7.75 (d, 2H), 7.69 (s, 1H),7.53-7.66 (m, 5H), 6.91 (d, 1H), 5.02 (t, 1H), 4.91-4.98 (m, 1H),4.49-4.59 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H),3.62 (t, 2H).

Example 372-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer (147 mg) from the separation of 315 mg of thecompound from Example 35 by Method 17b.

Analytical chiral HPLC [Method 18a]: R_(t)=13.98 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.72 (d, 1H), 7.74 (d, 2H), 7.69 (s, 1H),7.52-7.66 (m, 5H), 6.89 (d, 1H), 5.02 (t, 1H), 4.91-4.98 (m, 1H),4.49-4.60 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H),3.62 (t, 2H).

Example 382-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 278 mg (0.76 mmol) were introducedtogether with 184 mg (0.76 mmol) of the compound from Example 61A, 219mg (1.14 mmol) of EDC and 154 mg (1.14 mmol) of HOBt in 18 ml of DMF,then admixed with 265 μl (1.52 mmol) of N,N-diisopropylethylamine Themixture was stirred at RT overnight, admixed with 1 ml of 1Nhydrochloric acid and then purified by preparative HPLC (Method 10).This gave 310 mg (74% of theory) of the title compound.

LC-MS [Method 4]: R_(t)=1.03 min; MS [ESIpos]: m/z=553 (M+H)⁺

The two diastereomers were separated by preparative chromatography on achiral phase (Method 17e): see Examples 39 and 40.

Example 392-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer (134 mg) from the separation of 310 mg of thecompound from Example 38 by Method 17e. This product was purified toremove solvent residues by preparative HPLC (Method 10). This gave 99 mgof the title compound.

Analytical chiral HPLC [Method 18a]: R_(t)=2.12 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.79 (d, 1H), 7.73 (d, 2H), 7.64-7.71 (m,3H), 7.61 (d, 2H), 7.44-7.51 (m, 1H), 6.89 (d, 1H), 5.17-5.24 (m, 1H),5.14 (t, 1H), 4.52 (q [AB], 2H), 4.19-4.31 (m, 1H), 3.95 (dd, 1H), 3.82(dd, 1H), 3.54-3.62 (m, 1H), 3.44-3.53 (m, 1H).

Example 402-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer (156 mg) from the separation of 310 mg of thecompound from Example 38 by Method 17e. This product was also purifiedto remove solvent residues by preparative HPLC (Method 10). This gave128 mg of the title compound.

Analytical chiral HPLC [Method 18a]: R_(t)=5.59 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.79 (d, 1H), 7.74 (d, 2H), 7.65-7.70 (m,3H), 7.62 (d, 2H), 7.44-7.50 (m, 1H), 6.91 (d, 1H), 5.18-5.26 (m, 1H),5.15 (t, 1H), 4.46-4.57 (m [AB], 2H), 4.20-4.33 (m, 1H), 3.95 (dd, 1H),3.82 (dd, 1H), 3.54-3.62 (m, 1H), 3.44-3.53 (m, 1H).

Example 41N-[1-(2-Chlorophenyl)-2-hydroxyethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 355 mg (0.97 mmol), 223 mg (1.17 mmol)of EDC and 166 mg (1.17 mmol) of HOBt were stirred in 5 ml of DMF and 10ml of acetonitrile at RT for 20 min. This solution was added dropwise tothe solution of the amino alcohol from Example 66A (200 mg, 1.17 mmol)in 10 ml of acetonitrile, and the mixture was left to react at RT for 30min. Then 1 ml of 1N hydrochloric acid was added and the completereaction mixture was purified by preparative HPLC (Method 10). This gave400 mg (77% of theory) of the title compound.

LC-MS [Method 3]: R_(t)=1.15 min+1.16 min; in each case MS [ESIpos]:m/z=519 (M+H)⁺

The two diastereomers were separated by preparative chromatography on achiral phase (Method 17f): see Examples 42 and 43.

Example 42N-[1-(2-Chlorophenyl)-2-hydroxyethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

First-eluting diastereomer (186 mg) from the separation of 400 mg of thecompound from Example 41 by Method 17f. This product was also purifiedto remove solvent residues by preparative HPLC (Method 10). This gave153 mg of the title compound.

Analytical chiral HPLC [Method 18b]: R_(t)=5.30 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.75 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.46 (dd, 1H), 7.41 (dd, 1H), 7.25-7.36 (m, 2H), 6.89 (d, 1H), 5.24 (td,1H), 5.09 (t, 1H), 4.48-4.60 (m [AB], 2H), 4.20-4.32 (m, 1H), 3.96 (dd,1H), 3.82 (dd, 1H), 3.57-3.65 (m, 1H), 3.46-3.54 (m, 1H).

Example 43N-[1-(2-Chlorophenyl)-2-hydroxyethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

Last-eluting diastereomer (209 mg) from the separation of 400 mg of thecompound from Example 41 by Method 17f. This product was also purifiedto remove solvent residues by preparative HPLC (Method 10). This gave156 mg of the title compound.

Analytical chiral HPLC [Method 18b]: R_(t)=6.94 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.74 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H),7.46 (dd, 1H), 7.41 (dd, 1H), 7.24-7.36 (m, 2H), 6.91 (d, 1H), 5.25 (td,1H), 5.09 (t, 1H), 4.54 (s, 2H), 4.22-4.32 (m, 1H), 3.95 (dd, 1H), 3.82(dd, 1H), 3.57-3.65 (m, 1H), 3.45-3.54 (m, 1H).

Example 442-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{(2R)-1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}acetamide

Of the compound from Example 8A, 151 mg (0.42 mmol) were stirredtogether with 100 mg (0.46 mmol) of the compound from Example 69A, 119mg (0.62 mmol) of EDC and 84 mg (0.62 mmol) of HOBt in 4 ml of DMFovernight at RT, admixed with 1 ml of 1N hydrochloric acid and thenpurified completely by preparative HPLC (Method 10). This gave 91 mg(39% of theory) of the title compound.

LC-MS [Method 1] R_(t)=2.04 min; MS [ESIpos]: m/z=567 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.33 (s, 1H), 7.74 (d, 2H), 7.60-7.66 (m,4H), 7.48-7.57 (m, 2H), 6.89 (d, 1H), 5.12 (t, 1H), 4.48-4.60 (m [AB],2H), 4.20-4.32 (m, 1H), 3.95 (dd, 1H), 3.81 (dd, 1H), 3.55-3.66 (m, 2H),1.62 (s, 3H).

Example 45(2R)-2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propylcarbamate

Of the compound from Example 8A, 76 mg (0.21 mmol) were introducedtogether with 75 mg (0.25 mmol) of the compound from Example 71A, 48 mg(0.25 mmol) of EDC, 36 mg (0.25 mmol) of HOBt in 2 ml of DMF, 73 μl(0.42 mmol) of N,N-diisopropylethylamine were added, and the mixture wasstirred at RT overnight. It was admixed with 1 ml of 1N hydrochloricacid and then purified completely by preparative HPLC (Method 10). Thisgave 78 mg of the title compound (58% of theory).

LC-MS [Method 3] R_(t)=1.23 min; MS [ESIpos]: m/z=610 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.58 (s, 1H), 7.74 (d, 2H), 7.69 (d, 1H),7.57-7.66 (m, 4H), 7.54 (t, 1H), 6.87 (d, 1H), 6.40-6.75 (br.s, 2H),4.50 (s, 2H), 4.22-4.32 (m, 1H), 4.22 (d, 1H), 4.16 (d, 1H), 3.95 (dd,1H), 3.81 (dd, 1H), 1.68 (s, 3H).

Example 462-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethylcarbamate (diastereomer mixture)

Of the compound from Example 8A, 599 mg (1.64 mmol) were introducedtogether with 750 mg (1.96 mmol) of the compound from Example 60A, 377mg (1.96 mmol) of EDC and 279 mg (1.96 mmol) of HOBt in 20 ml of DMF,570 μl (3.27 mmol) of N,N-diisopropylethylamine were added and themixture was stirred at RT overnight. It was admixed with 5 ml of 1Nhydrochloric acid and then purified completely by preparative HPLC(Method 10). This gave 450 mg of the title compound (46% of theory).

LC-MS [Method 5] R_(t)=1.06 min; MS [ESIpos]: m/z=596 (M+H)⁺

The two diastereomers were separated by preparative chromatography on achiral phase (Method 17a): see Examples 47 and 48.

Example 472-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethylcarbamate (diastereomer I)

First-eluting diastereomer (209 mg) from the separation of 400 mg of thecompound from Example 46 by Method 17a. This product was also purifiedto remove solvent residues by preparative HPLC (Method 10). This gave169 mg of the title compound.

Analytical chiral HPLC [Method 18a]: R_(t)=7.44 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.88 (d, 1H), 7.70-7.78 (m, 3H), 7.56-7.70(m, 5H), 6.92 (d, 1H), 6.39-6.79 (br.s, 2H), 5.12-5.20 (m, 1H),4.45-4.60 (m [AB], 2H), 4.22-4.34 (m, 1H), 4.06-4.17 (m, 2H), 3.96 (dd,1H), 3.83 (dd, 1H).

Example 482-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethylcarbamate (diastereomer II)

Last-eluting diastereomer (190 mg) from the separation of 450 mg of thecompound from Example 46 by Method 17a. This product was also purifiedto remove solvent residues by preparative HPLC (Method 10). This gave167 mg of the title compound.

Analytical chiral HPLC [Method 18a]: R_(t)=17.99 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.89 (d, 1H), 7.70-7.77 (m, 3H), 7.56-7.70(m, 5H), 6.90 (d, 1H), 6.45-6.77 (br.s, 2H), 5.12-5.19 (m, 1H), 4.53 (s,2H), 4.21-4.33 (m, 1H), 4.07-4.17 (m, 2H), 3.96 (dd, 1H), 3.83 (dd, 1H).

Example 492-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[2-(trifluoromethyl)phenyl]ethylcarbamate (diastereomer mixture)

Of the compound from Example 8A, 428 mg (1.17 mmol) were stirredtogether with 269 mg (1.41 mmol) of EDC and 200 mg (1.41 mmol) of HOBtin 10 ml of DMF and 40 ml of acetonitrile at RT for 10 min. Thissolution was added dropwise to a solution of 400 mg (1.41 mmol) of thecompound from Example 63A and 408 μl (2.34 mmol) ofN,N-diisopropylethylamine in 50 ml of acetonitrile, and the mixture wasstirred at RT overnight. It was then admixed with 1 ml of 1Nhydrochloric acid and purified completely by preparative HPLC (Method10). This gave 580 mg of the title compound (83% of theory).

LC-MS [Method 2] R_(t)=2.24 min; MS [ESIpos]: m/z=596 (M+H)⁺

The two diastereomers were separated by preparative chromatography on achiral phase (Method 17d): see Examples 50 and 51.

Example 502-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[2-(trifluoromethyl)phenyl]ethylcarbamate (diastereomer I)

First-eluting diastereomer (297 mg) from the separation of 580 mg of thecompound from Example 49 by Method 17d. This product was also purifiedto remove solvent residues by preparative HPLC (Method 10). This gave239 mg of the title compound.

Analytical chiral HPLC [Method 18c]: R_(t)=3.26 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.97 (d, 1H), 7.68-7.78 (m, 5H), 7.62 (d,2H), 7.52 (t, 1H), 6.92 (d, 1H), 6.40-6.81 (2 br. s, 2H), 5.36-5.44 (m,1H), 4.49 (s, 2H), 4.21-4.33 (m, 1H), 4.13 (dd, 1H), 3.91-4.01 (m, 2H),3.81 (dd, 1H).

Example 512-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[2-(trifluoromethyl)phenyl]ethylcarbamate (diastereomer II)

Last-eluting diastereomer (280 mg) from the separation of 580 mg of thecompound from Example 49 by Method 17d. This product was also purifiedby preparative HPLC (Method 10). This gave 222 mg of the title compound.

Analytical chiral HPLC [Method 18c]: R_(t)=4.49 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.98 (d, 1H), 7.69-7.79 (m, 5H), 7.62 (d,2H), 7.49-7.56 (m, 1H), 6.90 (d, 1H), 6.40-6.81 (2 br. s, 2H), 5.35-5.42(m, 1H), 4.43-4.55 (m [AB], 2H), 4.19-4.32 (m, 1H), 4.13 (dd, 1H),3.92-4.01 (m, 2H), 3.82 (dd, 1H).

Example 52(2R)-2-(3-Chlorophenyl)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]ethylcarbamate

In the same way as for Example 1, from 203 mg (0.55 mmol) of thecompound from Example 8A and 153 mg (0.61 mmol) of the compound fromExample 65A, 183 mg of the title compound were obtained (59% of theory).

LC-MS [Method 3] R_(t)=1.19 min; MS [ESIpos]: m/z=562 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.79 (d, 1H), 7.76 (d, 2H), 7.63 (d, 2H),7.43 (s, 1H), 7.29-7.41 (m, 3H), 6.92 (d, 1H), 6.41-6.80 (2 br. s, 2H),5.02-5.11 (m, 1H), 4.43-4.59 (m, 2H), 4.22-4.34 (m, 1H), 4.02-4.15 (m,2H), 3.96 (dd, 1H), 3.83 (dd, 1H).

Example 532-(2-Chlorophenyl)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]ethylcarbamate (diastereomer mixture)

Of the compound from Example 8A, 606 mg (1.66 mmol) were stirredtogether with 382 mg (1.99 mmol) of EDC and 283 mg (1.99 mmol) of HOBtin 5 ml of DMF and 10 ml of acetonitrile at RT for 10 min. This solutionwas added dropwise to a solution of 500 mg (1.99 mmol) of the compoundfrom Example 68A and 578 μl (3.31 mmol) of N,N-diisopropylethylamine in10 ml of acetonitrile, and the mixture was stirred at RT for a further30 min. It was admixed with 1 ml of ¹N hydrochloric acid and thenpurified completely by preparative HPLC (Method 10). This gave 446 mg ofthe title compound (48% of theory).

LC-MS [Method 5] R_(t)=1.01 min; MS [ESIpos]: m/z=562 (M+H)⁺

The two diastereomers were separated by preparative chromatography on achiral phase (Method 17f): see Examples 54 and 55.

Example 542-(2-Chlorophenyl)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]ethylcarbamate (diastereomer I)

Last-eluting diastereomer (227 mg) from the separation of 443 mg of thecompound from Example 53 by Method 17f. This product was also purifiedto remove solvent residues by preparative HPLC (Method 10). This gave200 mg of the title compound.

Analytical chiral HPLC [Method 18b]: R_(t)=1.77 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.92 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H),7.51 (dd, 1H), 7.44 (dd, 1H), 7.29-7.40 (m, 2H), 6.92 (d, 1H), 6.43-6.80(2 br.s, 2H), 5.40-5.47 (m, 1H), 4.45-4.57 (m [AB], 2H), 4.21-4.32 (m,1H), 4.00-4.12 (m, 2H), 3.96 (dd, 1H), 3.82 (dd, 1H).

Example 552-(2-Chlorophenyl)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]ethylcarbamate (diastereomer II)

Last-eluting diastereomer (231 mg) from the separation of 443 mg of thecompound from Example 53 by Method 17f. This product was also purifiedto remove solvent residues by preparative HPLC (Method 10). This gave202 mg of the title compound.

Analytical chiral HPLC [Method 18b]: R_(t)=2.46 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.93 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.51 (dd, 1H), 7.45 (dd, 1H), 7.30-7.40 (m, 2H), 6.90 (d, 1H), 6.44-6.79(2 br.s, 2H), 5.38-5.46 (m, 1H), 4.52 (s, 2H), 4.21-4.32 (m, 1H),4.00-4.12 (m, 2H), 3.96 (dd, 1H), 3.82 (dd, 1H).

Example 56(2R)-2-(2-Chlorophenyl)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]propylcarbamate

Of the compound from Example 8A, 42 mg (0.12 mmol) were stirred togetherwith 32 mg (approximately 90% pure, 0.13 mmol) of the compound fromExample 75A, 26 mg (0.14 mmol) of EDC, 17 mg (0.14 mmol) of HOBt in 1.3ml of DMF at RT for 1 h. The mixture was then purified completely bypreparative HPLC (Method 10). This gave 42 mg of the title compound (63%of theory).

LC-MS [Method 4] R_(t)=1.01 min; MS [ESIpos]: m/z=576 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.58 (s, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.46 (dd, 1H), 7.37 (dd, 1H), 7.22-7.32 (br. s, 2H), 6.89 (d, 1H),6.45-6.75 (m, 2H), 4.45 (s, 2H), 4.36-4.44 (m, 2H), 4.20-4.33 (m, 1H),3.93 (dd, 1H), 3.80 (dd, 1H), 1.74 (s, 3H).

Example 57N-{2-(Carbamoylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

Of the compound from Example 11, 266 mg (0.45 mmol) were introduced in 6ml of methanol/water 1:1 and admixed with potassium cyanate (110 mg,1.36 mmol) at RT. The mixture was heated at 40° C. for 90 min. Followingcomplete reaction, the mixture was cooled to RT and purified completelyby preparative HPLC (Method 10). Drying in an HV gave 232 mg (84% oftheory) of the title compound.

LC-MS [Method 4]: R_(t)=1.02 min; MS [ESIpos]: m/z=595 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.78 (d, 1H), 7.76 (d, 2H), 7.54-7.66 (m,6H), 6.94 (d, 1H), 6.09 (t, 1H), 5.60 (s, 2H), 4.87-4.95 (m, 1H), 4.49(s, 2H), 4.25-4.38 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.29-3.38 (m,1H), 3.19-3.27 (m, 1H).

Example 58N-{2-(Carbamoylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

Of the compound from Example 12, 180 mg (0.31 mmol) were introduced in 3ml of methanol/water 1:1 and admixed with potassium cyanate (75 mg, 0.92mmol) at RT. The mixture was heated at 40° C. for 90 min. The methanolwas removed on a rotary evaporator and the aqueous residue was dilutedwith 20 ml of water. The precipitated solid was isolated by filtration,washed with a little water and dried in an HV. This gave 146 mg (76% oftheory) of the title compound.

LC-MS [Method 4]: R_(t)=1.02 min; MS [ESIpos]: m/z=595 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.79 (d, 1H), 7.77 (d, 2H), 7.54-7.66 (m,6H), 6.94 (d, 1H), 6.08 (t, 1H), 5.59 (s, 2H), 4.88-4.95 (m, 1H),4.41-4.56 (m [AB], 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.84 (dd, 1H),3.29-3.38 (m, 1H), 3.16-3.27 (m, 1H).

Example 59N-{2-(Carbamoylamino)-1-[2-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

In the same way as for Example 57, from 230 mg (0.39 mmol) of thecompound from Example 13, the title compound was obtained (190 mg, 79%of theory).

LC-MS [Method 3]: R_(t)=1.17 min; MS [ESIpos]: m/z=595 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.84 (d, 1H), 7.77 (d, 2H), 7.62-7.74 (m,5H), 7.48 (t, 1H), 6.95 (d, 1H), 6.22 (t, 1H), 5.58 (s, 2H), 5.06-5.13(m, 1H), 4.39-4.51 (m [AB], 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.83(dd, 1H), 3.21-3.27 (m, 2H).

Example 60N-{2-(Carbamoylamino)-1-[2-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

In the same way as for Example 57, but at RT, from 50 mg (85 μmol) ofthe compound from Example 14, the title compound was obtained (41 mg,81% of theory).

LC-MS [Method 2]: R_(t)=2.19 min; MS [ESIpos]: m/z=595 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.84 (d, 1H), 7.76 (d, 2H), 7.60-7.72 (m,5H), 7.48 (t, 1H), 6.93 (d, 1H), 6.23 (t, 1H), 5.59 (s, 2H), 5.05-5.12(m, 1H), 4.45 (s, 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H),3.15-3.34 (m, 2H).

Example 61N-[2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

In the same way as for Example 57, from 116 mg (0.20 mmol) of thecompound from Example 15, the title compound was obtained (90 mg, 77% oftheory).

LC-MS [Method 3]: R_(t)=1.19 min; MS [ESIpos]: m/z=595 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.91 (d, 1H), 7.77 (d, 2H), 7.63 (d, 2H),7.52-7.59 (m, 1H), 7.34-7.40 (m, 2H), 6.94 (d, 1H), 6.19 (t, 1H), 5.60(s, 2H), 5.12-5.20 (m, 1H), 4.40-4.55 (q [AB], 2H), 4.25-4.37 (m, 1H),3.97 (dd, 1H), 3.84 (dd, 1H), 3.28-3.37 (m, 1H), 3.19-3.28 (m, 1H).

Example 62N-[2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

In the same way as for Example 57, from 177 mg (0.30 mmol) of thecompound from Example 16, the title compound was obtained (153 mg, 85%of theory).

LC-MS [Method 3]: R_(t)=1.20 min; MS [ESIpos]: m/z=595 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.91 (d, 1H), 7.76 (d, 2H), 7.63 (d, 2H),7.52-7.59 (m, 1H), 7.34-7.40 (m, 2H), 6.94 (d, 1H), 6.19 (t, 1H), 5.61(s, 2H), 5.12-5.19 (m, 1H), 4.48 (s, 2H), 4.26-4.38 (m, 1H), 3.97 (dd,1H), 3.83 (dd, 1H), 3.29-3.38 (m, 1H), 3.18-3.27 (m, 1H).

Example 632-[({3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethylcarbamate (Racemate)

Of the compound from Example 77A, 100 mg (0.29 mmol) were introduced in3 ml of DMF and admixed with 98.3 mg (0.35 mmol) of the compound fromExample 60A, 66.1 mg (0.35 mmol) of EDC, 49 mg (0.35 mmol) of HOBt and75 μl (0.43 mmol) of N,N-diisopropylethylamine. The mixture was stirredat RT for 30 min and then admixed with 1 ml of 1N hydrochloric acid andpurified by preparative HPLC (Method 10). This gave 140 mg (84% oftheory) of the title compound.

LC/MS [Method 5]: R_(t)=1.16 min; m/z=578 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.90 (d, 1H), 7.73 (s, 1H), 7.57-7.69 (m,7H), 7.18 (dq, 1H), 6.87 (dq, 1H), 5.09-5.27 (m, 1H), 4.47-4.68 (m [AB],2H), 3.99-4.21 (m, 2H).

The enantiomers from Example 63 were separated by preparativechromatography on a chiral phase (Method 15b): see Example 64 andExample 65.

Example 642-[({3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethylcarbamate (Enantiomer I)

First-eluting enantiomer (64 mg) from the separation of 135 mg of thecompound from Example 63 by Method 15b.

Analytical chiral HPLC [Method 16]: R_(t)=1.50 min.

Example 652-[({3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethylcarbamate (Enantiomer II)

Last-eluting enantiomer (62 mg) from the separation of 135 mg of thecompound from Example 63 by Method 15b.

Analytical chiral HPLC [Method 16]: R_(t)=1.90 min.

Example 662-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{3-hydroxy-1-[3-(trifluoromethyl)phenyl]propyl}acetamide(diastereomer mixture)

In the same way as for Example 24, from 100 mg (0.27 mmol) of thecompound from Example 8A and 84 mg (0.33 mmol) of the compound fromExample 78A, the title compound was obtained: 112 mg (72% of theory).

LC-MS [Method 3] R_(t)=1.22 min; MS [ESIpos]: m/z=567 (M+H)⁺

The diastereomers from Example 66 were separated by preparativechromatography on a chiral phase (Method 8): see Example 67 and Example68.

Example 672-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{3-hydroxy-1-[3-(trifluoromethyl)phenyl]propyl}acetamide(diastereomer I)

First-eluting diastereomer (50 mg) from the chromatographic separationof 112 mg of the compound from Example 66 by Method 8.

Analytical chiral HPLC [Method 9]: R_(t)=3.25 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.71 (d, 1H), 7.73 (dd, 2H), 7.54-7.66 (m,6H), 6.90 (d, 1H), 4.97-5.05 (m, 1H), 4.58 (t, 1H), 4.42-4.56 (m [AB],2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.32-3.47 (m, 2H),1.77-1.96 (m, 2H).

Example 682-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{3-hydroxy-1-[3-(trifluoromethyl)phenyl]propyl}acetamide(diastereomer II)

Last-eluting diastereomer (47 mg) from the chromatographic separation of112 mg of the compound from Example 66 by Method 8.

Analytical chiral HPLC [Method 9]: R_(t)=4.41 min

¹H NMR (DMSO-d₆, 400 MHz): δ=8.70 (d, 1H), 7.74 (dd, 2H), 7.53-7.66 (m,6H), 6.92 (d, 1H), 4.98-5.08 (m, 1H), 4.59 (t, 1H), 4.49 (s, 2H),4.21-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.32-3.47 (m, 2H),1.77-1.96 (m, 2H).

Example 692-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{(1S)-3-hydroxy-1-[2-(trifluoromethyl)phenyl]propyl}acetamide

In the same way as for Example 49, from 167 mg (0.46 mmol) of thecompound from Example 8A and 140 mg (0.55 mmol) of the compound fromExample 80A, the title compound was obtained: 152 mg (58% of theory).

LC-MS [Method 3] R_(t)=1.21 min; MS [ESIpos]: m/z=567 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.75 (d, 1H), 7.74 (d, 2H), 7.64-7.70 (m,3H), 7.62 (d, 2H), 7.41-7.50 (m, 1H), 6.90 (d, 1H), 5.20-5.28 (m, 1H),4.57 (t, 1H), 4.40-4.55 (m [AB], 2H), 4.21-4.32 (m, 1H), 3.95 (dd, 1H),3.81 (dd, 1H), 3.41-3.56 (m, 2H), 1.69-1.87 (m, 2H).

Example 70(3S)-3-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[2-(trifluoromethyl)phenyl]propylcarbamate

In the same way as for Example 49, from 194 mg (0.53 mmol) of thecompound from Example 8A and 190 mg (0.64 mmol) of the compound fromExample 81A, the title compound was obtained: 138 mg (43% of theory).

LC-MS [Method 5] R_(t)=1.04 min; MS [ESIpos]: m/z=610 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.84 (d, 1H), 7.65-7.76 (m, 5H), 7.62 (d,2H), 7.42-7.51 (m, 1H), 6.90 (d, 1H), 6.33-6.58 (br. s, 2H), 5.20-5.28(m, 1H), 4.57 (t, 1H), 4.42-4.59 (m [AB], 2H), 4.01-4.08 (m, 1H),3.86-3.99 (m, 2H), 3.82 (dd, 1H), 1.83-1.99 (m, 2H).

Example 713-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-(2,3-dichlorophenyl)propylcarbamate (diastereomer mixture)

In the same way as for Example 1, from 630 mg (1.72 mmol) of thecompound of Example 8A and 568 mg (1.90 mmol) of the compound fromExample 88A, the title compound was obtained: 809 mg (77% of theory).

LC-MS [Method 3] R_(t)=1.22+1.23 min; MS [ESIpos]: m/z=610 (M+H)⁺

The diastereomers from Example 71 were separated by preparativechromatography on a chiral phase (Method 13): see Example 72 and Example73.

Example 723-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-(2,3-dichlorophenyl)propylcarbamate (diastereomer I)

First-eluting diastereomer (270 mg) from the chromatographic separationof 800 mg of the compound from Example 71 by Method 13.

LC-MS [Method 5] R_(t)=1.07 min; MS [ESIpos]: m/z=610 (M+H)⁺

Analytical chiral HPLC [Method 14]: R_(t)=5.61 min.

¹H NMR (DMSO-d₆, 400 MHz): δ=8.83-8.90 (m, 1H), 7.75 (d, 2H), 7.63 (d,2H), 7.54 (d, 1H), 7.44 (dd, 1H), 7.37 (t, 1H), 6.91 (d, 1H), 6.32-6.70(br. s, 2H), 5.25-5.33 (m, 1H), 4.47-4.60 (m [AB], 2H), 4.20-4.34 (m,1H), 3.88-4.04 (m, 3H), 3.82 (dd, 1H), 1.83-2.02 (m, 2H).

Example 733-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-(2,3-dichlorophenyl)propylcarbamate (diastereomer II)

Last-eluting diastereomer (270 mg) from the chromatographic separationof 800 mg of the compound from Example 71 by Method 13.

LC-MS [Method 5] R_(t)=1.07 min; MS [ESIpos]: m/z=610 (M+H)⁺

Analytical chiral HPLC [Method 14]: R_(t)=14.96 min.

¹H NMR (DMSO-d₆, 400 MHz): δ=8.87 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.55 (dd, 1H), 7.44 (dd, 1H), 7.38 (t, 1H), 6.90 (d, 1H), 6.34-6.69(br.s, 2H), 5.24-5.32 (m, 1H), 4.44-4.62 (m [AB], 2H), 4.21-4.32 (m,1H), 3.88-4.05 (m, 3H), 3.82 (dd, 1H), 1.83-2.02 (m, 2H)

Example 742-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[(1R)-1-(2,3-dimethylphenyl)-2-hydroxyethyl]acetamide

Of the compound from Example 8A, 50 mg (0.14 mmol), 39 mg (0.21 mmol) ofEDC and 28 mg (0.21 mmol) of HOBt were stirred together in 1.2 ml of DMFat RT for 20 min, then admixed with 30 mg of(2R)-2-amino-2-(2,3-dimethylphenyl)ethanol hydrochloride (0.15 mmol) and31 μl (0.18 mmol) of N,N-diisopropylamine. The mixture was stirred at RTfor 2 h. Subsequently the complete reaction mixture was purified bypreparative HPLC (Method 10). This gave 58 mg (81% of theory) of thetitle compound.

LC-MS [Method 5]: R_(t)=1.04 min; m/z=513 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.60 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.16 (dd, 1H), 7.01-7.08 (m, 2H), 6.89 (d, 1H), 5.08-5.16 (m, 1H), 4.94(t, 1H), 4.41-4.56 (m [AB], 2H), 4.21-4.32 (m, 1H), 3.96 (dd, 1H), 3.82(dd, 1H), 3.41-3.56 (m, 2H), 2.23 (s, 3H), 2.20 (s, 3H).

Example 752-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[(1R)-1-(3-cyanophenyl)-2-hydroxyethyl]acetamide

In the same way as for Example 74, from 50 mg of the compound fromExample 8A (0.14 mmol) and 30 mg of(2R)-2-amino-2-(3-cyanophenyl)ethanol hydrochloride (0.15 mmol), 42 mg(60% of theory) of the title compound were obtained.

LC-MS [Method 5]: R_(t)=0.95 min; m/z=510 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.68 (d, 1H), 7.79 (s, 1H), 7.70-7.77 (m,3H), 7.68 (d, 1H), 7.62 (d, 2H), 7.54 (t, 1H), 6.90 (d, 1H), 5.03 (t,1H), 4.87-4.94 (m, 1H), 4.56 (s, 2H), 4.22-4.33 (m, 1H), 3.97 (dd, 1H),3.83 (dd, 1H), 3.58-3.64 (m, 2H)

Example 762-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[(1R)-1-(3-chlorophenyl)-2-hydroxyethyl]acetamide

In the same way as for Example 74, from 50 mg of the compound fromExample 8A (0.14 mmol) and 31 mg of(2R)-2-amino-2-(3-chlorophenyl)ethanol hydrochloride (0.15 mmol), 54 mg(76% of theory) of the title compound were obtained.

LC-MS [Method 5]: R_(t)=1.03 min; m/z=519 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.62 (d, 1H), 7.76 (d, 2H), 7.62 (d, 2H),7.39 (s, 1H), 7.26-7.38 (m, 3H), 6.92 (d, 1H), 5.00 (t, 1H), 4.82-4.90(m, 1H), 4.47-4.59 (m [AB], 2H), 4.21-4.35 (m, 1H), 3.96 (dd, 1H), 3.83(dd, 1H), 3.55-3.63 (m, 2H)

Example 77N-[(2R)-2-(2-Chlorophenyl)-1-hydroxypropan-2-yl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide

In the same way as for Example 1, from 62 mg of the compound fromExample 8A (0.17 mmol) and 49 mg of the compound from Example 74A (0.19mmol), 33 mg (36% of theory) of the title compound were obtained.

LC-MS [Method 4]: R_(t)=1.02 min; m/z=533 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.27 (s, 1H), 7.74 (d, 2H), 7.62 (d, 2H),7.47 (dd, 1H), 7.33 (dd, 1H), 7.18-7.28 (m, 2H), 6.89 (d, 1H), 5.11 (t,1H), 4.48 (s, 2H), 4.19-4.33 (m, 1H), 3.86-3.97 (m, 2H), 3.73-3.85 (m,2H), 1.68 (s, 3H).

Example 782-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{3,3,3-trifluoro-2-hydroxy-1-[3-(trifluoromethyl)phenyl]propyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 113 mg (0.31 mmol), 93 mg (0.34 mmol)of the amino alcohol from Example 99A, 83 mg (0.43 mmol) of EDC and 59mg (0.43 mmol) of HOBt were stirred together in 4.3 ml of DMF at RT for2 h. Subsequently the reaction mixture was purified by preparative HPLC(Method 10). This gave 162 mg (80% of theory) of the title compound as amixture of 4 diastereomers.

LC-MS [Method 5]: R_(t)=1.14 min; MS [ESIpos]: m/z=621 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.97+8.93+8.92 (3×d, 1H), 7.86+7.81 (2×s,1H), 7.55-7.77 (m, 7H), 6.82-6.93 (5×d, 1.4H), 6.72 (d, 0.6H), 5.41 (brd, 0.4H), 5.15-5.21 (m, 0.6H), 4.42-4.66 (m, 2H), 4.20-4.40 (m, 2H),3.92-4.01 (br d, 1H), 3.77-3.87 (2×dd, 1H).

Example 792-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[1-(2,3-dichlorophenyl)-3-hydroxypropyl]acetamide(diastereomer mixture)

Of the compound from Example 8A, 100 mg (0.27 mmol) were dissolved in 4ml of DMF, admixed with 68 mg (0.36 mmol) of EDC and with 44 mg (0.33mmol) of HOBt, and stirred at room temperature for 10 minutes.Subsequently 66 mg (0.30 mmol) of the compound from Example 90A wereadded and the mixture was left with stirring at room temperature for 16h. For work-up, 10 ml of water were added and the mixture was extractedwith twice 10 ml of ethyl acetate. The combined organic phases weredried over sodium sulphate, filtered and concentrated on a rotaryevaporator. The crude product was purified by preparative HPLC [Method19]. This gave 44 mg (28% of theory) of the target compound.

LC-MS [Method 3] R_(t)=1.24 min; MS [ESIpos]: m/z=567/569/571 (M+H)⁺

The diastereomer mixture from Example 79 was separated into thediastereomers by preparative HPLC on chiral phase [Method 11d]: seeExamples 80 and 81.

Example 802-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[1-(2,3-dichlorophenyl)-3-hydroxypropyl]acetamide(diastereomer I)

First-eluting diastereomer from the separation of Example 79.

Yield: 21 mg (14% of theory)

R_(t)=4.04 min [Method 12c]

LC-MS [Method 5] R_(t)=1.07 min; MS [ESIpos]: m/z=567/569/571 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=1.92-2.03 (m, 1H), 2.04-2.15 (m, 1H), 3.02(br.s, 1H), 3.55-3.66 (m, 1H), 3.68-3.78 (m, 1H), 3.93-4.05 (m, 2H),4.47-4.60 (m, 2H), 4.70 (d, 1H), 5.26 (d, 1H), 5.49 (td, 1H), 7.15-7.23(m, 1H), 7.27-7.31 (m, 1H), 7.35-7.42 (m, 1H), 7.50 (d, 2H), 7.57-7.71(m, 3H).

Example 812-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[1-(2,3-dichlorophenyl)-3-hydroxypropyl]acetamide(diastereomer II)

Last-eluting diastereomer from the separation of Example 79.

Yield: 20 mg (13% of theory)

R_(t)=4.84 min [Method 12c]

LC-MS [Method 5] R_(t)=1.07 min; MS [ESIpos]: m/z=567 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=1.88-2.00 (m, 1H), 2.04-2.15 (m, 1H), 3.05(br.s, 1H), 3.54-3.68 (m, 1H), 3.70-3.81 (m, 1H), 3.91-4.06 (m, 2H),4.51 (d, 1H), 4.54-4.62 (m, 1H), 4.69 (d, 1H), 5.22 (d, 1H), 5.49 (td,1H), 7.10-7.23 (m, 2H), 7.37 (dd, 1H), 7.45 (d, 1H), 7.52 (d, 2H), 7.65(d, 2H).

Example 82N-[1-(2-Chlorophenyl)-3-hydroxypropyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 100 mg (0.27 mmol) were dissolved in 1ml of DMF, admixed with 79 mg (0.41 mmol) of EDC and 55 mg (0.41 mmol)of HOBt and stirred at room temperature for 10 minutes. Subsequently 67mg (0.30 mmol) of 3-amino-3-(2-chlorophenyl)propan-1-ol hydrochlorideand also 63 μl (0.38 mmol) of N,N-diisopropylethylamine were added andthe mixture was left with stirring at room temperature for 16 h. Forwork-up, 10 ml of water were added and the mixture was extracted withtwice 10 ml of ethyl acetate. The combined organic phases were driedover magnesium sulphate, filtered and concentrated on a rotaryevaporator. The crude product was purified by preparative HPLC [Method19]. This gave 93 mg (64% of theory) of the target compound.

LC-MS [Method 3] R_(t)=1.16 min; MS [ESIpos]: m/z=533/535 (M+H)⁺

The diastereomer mixture from Example 82 was separated into thediastereomers by preparative HPLC on chiral phase [Method 8a]: seeExamples 83 and 84.

Example 83N-[1-(2-Chlorophenyl)-3-hydroxypropyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

First-eluting diastereomer from the separation of Example 82.

Yield: 34 mg (23% of theory)

R_(t)=2.00 min [Method 14]

LC-MS [Method 6] R_(t)=2.21 min; MS [ESIpos]: m/z=533/535 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=1.93-2.15 (m, 2H), 3.26 (br.s, 1H), 3.57-3.67(m, 1H), 3.68-3.77 (m, 1H), 3.89-4.05 (m, 2H), 4.48-4.62 (m, 2H), 4.72(d, 1H), 5.36-5.45 (m, 1H), 5.49 (td, 1H), 7.17-7.25 (m, 1H), 7.35 (d,2H), 7.49 (d, 2H), 7.57 (d, 1H), 7.64 (d, 2H).

Example 84N-[1-(2-Chlorophenyl)-3-hydroxypropyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

Last-eluting diastereomer from the separation of Example 82.

Yield: 38 mg (26% of theory)

R_(t)=2.92 min [Method 14]

LC-MS [Method 1] R_(t)=1.86 min; MS [ESIpos]: m/z=533/535 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=1.90-2.15 (m, 2H), 3.56-3.68 (m, 1H),3.69-3.79 (m, 1H), 3.87-4.06 (m, 2H), 4.50 (d, 1H), 4.53-4.63 (m, 1H),4.70 (d, 1H), 5.48 (td, 1H), 7.16-7.23 (m, 2H), 7.30-7.40 (m, 2H), 7.51(d, 2H), 7.65 (d, 2H).

Example 852-[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[1-(2-chlorophenyl)-3-hydroxypropyl]acetamide(Racemate)

In the same way as for the compound from Example 82, 30 mg (0.10 mmol)of[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid (for preparation see WO 2007/134862, Example 88A) were reacted.This gave 14 mg (30% of theory) of the target compound.

LC-MS [Method 3] R_(t)=1.12 min; MS [ESIpos]: m/z=461/463 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.67-0.79 (m, 2H), 0.97-1.09 (m, 2H),1.92-2.15 (m, 2H), 2.67 (br.s, 1H), 2.99 (tt, 1H), 3.57-3.79 (m, 2H),4.45-4.65 (m, 2H), 5.51 (td, 1H), 7.17-7.25 (m, 2H), 7.30-7.39 (m, 2H),7.47 (d, 2H), 7.68 (d, 2H).

Example 862-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[3-hydroxy-1-(2-methylphenyl)propyl]acetamide(diastereomer mixture)

Of the compound from Example 8A, 250 mg (0.68 mmol) were dissolved in 5ml of DMF, admixed with 170 mg (0.89 mmol) of EDC and with 111 mg (0.82mmol) of HOBt and stirred at room temperature for 10 minutes.Subsequently 124 mg (0.75 mmol) of 3-amino-3-(2-methylphenyl)propan-1-olwere added and the mixture was left with stirring at room temperaturefor 16 h. For work-up, 10 ml of water were added and the mixture wasextracted with twice 10 ml of ethyl acetate. The combined organic phaseswere dried over sodium sulphate, filtered and concentrated on a rotaryevaporator. The crude product was purified by preparative HPLC [Method19]. This gave 181 mg (52% of theory) of the target compound.

LC-MS [Method 1] R_(t)=1.84 and 1.86 min; MS [ESIpos]: m/z=513 (M+H)⁺

The diastereomer mixture from Example 86 was separated into thediastereomers by preparative HPLC on chiral phase [Method 8a]: seeExamples 87 and 88.

Example 872-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[3-hydroxy-1-(2-methylphenyl)propyl]acetamide(diastereomer I)

First-eluting diastereomer from the separation of Example 86.

Yield: 86 mg (25% of theory)

R_(t)=1.80 min [Method 14]

LC-MS [Method 6] R_(t)=2.19 min; MS [ESIpos]: m/z=513 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.65-1.91 (m, 2H), 2.32 (s, 3H), 3.33-3.48(m, 2H), 3.81 (dd, 1H), 3.95 (dd, 1H), 4.20-4.34 (m, 1H), 4.35-4.57 (m,3H), 5.06-5.18 (m, 1H), 6.90 (d, 1H), 7.11 (d, 2H), 7.14-7.21 (m, 1H),7.31 (d, 1H), 7.62 (d, 2H), 7.74 (d, 2H), 8.59 (d, 1H).

Example 882-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[3-hydroxy-1-(2-methylphenyl)propyl]acetamide(diastereomer II)

Last-eluting diastereomer from the separation of Example 86.

Yield: 87 mg (25% of theory)

R_(t)=2.76 min [Method 14]

LC-MS [Method 6] R_(t)=2.21 min; MS [ESIpos]: m/z=513 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.68-1.89 (m, 2H), 2.32 (s, 3H), 3.34-3.49(m, 2H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.20-4.33 (m, 1H), 4.45 (dd, 2H),4.53 (t, 1H), 5.08-5.18 (m, 1H), 6.91 (d, 1H), 7.11 (d, 2H), 7.14-7.20(m, 1H), 7.31 (d, 1H), 7.59-7.65 (m, 2H), 7.74 (d, 2H), 8.58 (d, 1H).

Example 892-[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-hydroxy-1-(3-methoxyphenyl)propyl]acetamide(Racemate)

In the same way as for the compound from Example 86, 30 mg (0.10 mmol)of[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid (for preparation see WO 2007/134862, Example 88A) and 20 mg (0.11mmol) of 3-amino-3-(3-methoxyphenyl)propan-1-ol were reacted. This gave30 mg (63% of theory) of the target compound.

LC-MS [Method 3] R_(t)=1.08 min; MS [ESIpos]: m/z=456 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.69-0.80 (m, 2H), 0.97-1.08 (m, 2H),1.78-1.90 (m, 1H), 2.05-2.17 (m, 1H), 2.86 (br.s, 1H), 2.98 (tt, 1H),3.57-3.74 (m, 2H), 3.77 (s, 3H), 4.55 (q, 2H), 5.20 (td, 1H), 6.75-6.84(m, 2H), 6.87 (d, 1H), 7.04 (d, 1H), 7.21-7.25 (m, 1H), 7.46 (d, 2H),7.67 (d, 2H).

Example 902-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(3,3,3-trifluoro-1-phenylpropyl)acetamide(diastereomer mixture)

In the same way as for the compound from Example 86, 50 mg (0.14 mmol)of the compound from Example 8A and 28 mg (0.15 mmol) of3,3,3-trifluoro-1-phenylpropan-1-amine were reacted. This gave 44 mg(59% of theory) of the target compound.

LC-MS [Method 3] R_(t)=1.30 min; MS [ESIpos]: m/z=537 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=2.53-2.81 (m, 2H), 3.92-4.07 (m, 2H),4.43-4.67 (m, 4H), 5.28-5.37 (m, 1H), 6.70 (dd, 1H), 7.27-7.40 (m, 5H),7.46-7.56 (m, 4H).

Example 91N-[1-(3-Chlorophenyl)-3-hydroxypropyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

In the same way as for the compound from Example 79, from 50 mg (0.14mmol) of the compound from Example 8A and 28 mg (0.15 mmol) of3-amino-3-(3-chlorophenyl)propan-1-ol, 48 mg (65% of theory) of thetitle compound were obtained.

LC-MS [Method 1] R_(t)=1.89 and 1.90 min; MS [ESIpos]: m/z=533 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=1.78-1.91 (m, 1H), 2.00-2.15 (m, 1H), 3.14(br.s, 0.5H), 3.25 (br.s, 0.5H), 3.54-3.74 (m, 2H), 3.89-4.06 (m, 2H),4.43-4.74 (m, 3H), 5.10-5.22 (m, 1H), 5.28-5.40 (m, 1H), 7.10-7.30 (m,4.5H), 7.42 (d, 0.5H), 7.46-7.53 (m, 2H), 7.64 (m, 2H) (partialresolution of the twofold set of signals of the diastereomer mixture).

Example 922-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[1-(2-fluorophenyl)-3-hydroxypropyl]acetamide(diastereomer mixture)

Of the compound from Example 93A, 39 mg (0.07 mmol) were dissolved in 2ml of 1,2-dimethoxyethane and admixed at room temperature in successionwith 4.1 mg (0.11 mmol) of sodium borohydride and with 0.6 mg (0.014mmol) of lithium chloride. Subsequently the mixture was stirred at 85°C. for 16 h. For work-up, 10 ml of saturated aqueous sodium potassiumtartrate solution were added and the mixture was extracted with threetimes 10 ml of ethyl acetate. The combined organic phases were driedover magnesium sulphate, filtered and concentrated on a rotaryevaporator. The crude product was purified by preparative HPLC [Method19]. This gave 19 mg (49% of theory) of the target compound.

LC-MS [Method 6] R_(t)=2.13 min; MS [ESIpos]: m/z=517 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=1.92-2.11 (m, 2H), 3.55-3.76 (m, 2H),3.89-4.07 (m, 2H), 4.43-4.77 (m, 3H), 5.31-5.44 (m, 1H), 6.98-7.15 (m,2H), 7.17-7.39 (m, 2H), 7.46-7.54 (m, 2H), 7.59-7.68 (m, 2H).

Example 933-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-(2-fluorophenyl)propylcarbamate (diastereomer mixture)

Of the compound from Example 8A, 354 mg (0.97 mmol) were dissolved in 3ml of DMF, admixed with 260 mg (1.36 mmol) of EDC and with 183 mg (1.36mmol) of HOBt and stirred at room temperature for 10 minutes.Subsequently 265 mg (1.07 mmol) of the compound from Example 89A andalso 192 μl (1.16 mmol) of N,N-diisopropylethylamine were added and themixture was left with stirring at room temperature for 2 h. For work-up,it was diluted with 5 ml of DMF and the crude product was purifieddirectly by preparative HPLC [Method 19]. This gave 420 mg (77% oftheory) of the target compound.

LC-MS [Method 5] R_(t)=0.99 min; MS [ESIpos]: m/z=560 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.74-2.09 (m, 2H), 3.36-3.47 (m, 1H),3.72-4.03 (m, 3H), 4.19-4.36 (m, 1H), 4.38-4.60 (m, 2H), 5.10-5.25 (m,1H), 6.50 (br.s, 2H), 6.86-6.95 (m, 1H), 7.09-7.23 (m, 2H), 7.24-7.36(m, 1H), 7.36-7.46 (m, 1H), 7.56-7.67 (m, 2H), 7.69-7.78 (m, 2H),8.57-8.77 (m, 1H).

Example 942-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-(3,3,3-trifluoro-2-hydroxy-1-phenylpropyl)acetamide(diastereomer mixture)

In the same way as for the compound from Example 93, 100 mg (0.27 mmol)of the compound from Example 8A and 73 mg (0.30 mmol) of3-amino-1,1,1-trifluoro-3-phenylpropan-2-ol hydrochloride were reacted.This gave 102 mg (63% of theory) of the target compound as adiastereomer mixture.

LC-MS [Method 2] R_(t)=2.29 min; MS [ESIpos]: m/z=552 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.88-4.07 (m, 2H), 4.15-4.26 (m, 1H),4.42-4.75 (m, 5H), 4.97-5.09 (m, 1H), 5.37 (dd, 1H), 7.15-7.41 (m, 5H),7.44-7.53 (m, 2H), 7.56-7.65 (m, 2H).

Example 952-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[1-(2,3-difluorophenyl)-2-hydroxyethyl]acetamide(diastereomer mixture)

Of the compound from Example 8A, 128 mg (0.33 mmol) were dissolved in 1ml of DMF, admixed with 83 mg (0.43 mmol) of EDC and with 58 mg (0.43mmol) of HOBt and stirred at room temperature for 10 minutes.Subsequently 79 mg (0.37 mmol) of the compound from Example 92A and also51 μl (0.37 mmol) of triethylamine were added and the mixture was leftwith stirring at room temperature for 16 h. For work-up, 10 ml of waterwere added and the mixture was extracted with twice 10 ml of ethylacetate. The combined organic phases were dried over sodium sulphate,filtered and concentrated on a rotary evaporator. The crude product waspurified by preparative HPLC [Method 19]. This gave 118 mg (68% oftheory) of the target compound.

LC-MS [Method 4] R_(t)=0.99 min; MS [ESIpos]: m/z=521 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.13-3.25 (m, H), 3.45-3.52 (m, H), 3.58-3.70(m, H), 3.74-3.83 (m, H), 3.83-4.10 (m, H), 4.46-4.57 (m, H), 4.58-4.78(m, H), 5.25 (d, H), 5.29-5.40 (m, H), 5.62 (d, H), 6.95 (d, H),6.99-7.16 (m, H), 7.48 (dd, H), 7.54 (d, H), 7.62 (d, H), 7.68 (d, H)(partial resolution of the twofold set of signals of the diastereomermixture).

Example 962-[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(Racemate)

In the same way as for the compound from Example 95, 48 mg (0.16 mmol)of[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid (for preparation see WO 2007/134862, Example 88A) and 58 mg (0.18mmol) of the compound from Example 91A were reacted. This gave 61 mg(77% of theory) of the target compound.

LC-MS [Method 4] R_(t)=1.02 min; MS [ESIpos]: m/z=481 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=0.72-0.82 (m, 2H), 0.99-1.09 (m, 2H),2.36-2.45 (m, 1H), 3.00 (spt, 1H), 3.83-4.00 (m, 2H), 4.53-4.67 (m, 2H),5.13-5.20 (m, 1H), 7.43-7.50 (m, 3H), 7.50-7.58 (m, 3H), 7.69 (d, 2H).

Example 97 Methyl{2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethyl}carbamate(diastereomer mixture)

Of the compound from Example 8A, 393 mg (1.07 mmol), 353 mg (1.18 mmol)of the compound from Example 138A, 247 mg (1.29 mmol) of EDC, 174 mg(1.29 mmol) of HOBt and 225 μl (1.29 mmol) of N,N-diisopropylethylaminewere stirred in 13 ml of DMF at RT for one hour. The entire reactionsolution was purified by preparative HPLC [Method 23]. The appropriatefraction was freed from the solvents on a rotary evaporator and theresidue was dried in an HV. This gave 416 mg (64% of theory) of thetitle compound as a diastereomer mixture (ratio 20:78 according toanalytical HPLC [Method 22]).

LC-MS [Method 5] R_(t)=1.09 min; MS [ESIpos]: m/z=610 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 21a]: see Example 98 and Example 99.

Example 98 Methyl{2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethyl}carbamate(diastereomer I)

First-eluting diastereomer (51 mg, d.e. >99.5%) from the chromatographicseparation of 416 mg of the compound from Example 97 [Method 21a].

Chiral analytical HPLC [Method 22]: R_(t)=3.52 min

LC-MS [Method 4] R_(t)=1.11 min; MS [ESIpos]: m/z=610 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.22-3.40 (m, 2H), 3.47 (s, 3H), 3.83 (dd,1H), 3.96 (dd, 1H), 4.22-4.35 (m, 1H), 4.51 (s, 2H), 5.02 (q, 1H), 6.91(d, 1H), 7.26 (t, 1H), 7.54-7.65 (m, 5H), 7.66 (s, 1H), 7.75 (d, 2H),8.68 (d, 1H).

Example 99 Methyl{2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethyl}carbamate(diastereomer II)

Last-eluting diastereomer from the chromatographic separation of 416 mgof the compound from Example 97 by Method 21a. The resulting product(238 mg, d.e. >99.5%) was further purified by preparative HPLC [Method20]. This gave 180 mg of the title compound.

Chiral analytical HPLC [Method 22]: R_(t)=4.81 min

LC-MS [Method 5] R_(t)=1.11 min; MS [ESIpos]: m/z=610 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.23-3.39 (m, 2H), 3.47 (s, 3H), 3.83 (dd,1H), 3.97 (dd, 1H), 4.21-4.33 (m, 1H), 4.44-4.57 (m, 2H [AB]), 5.01 (q,1H), 6.88 (d, 1H), 7.26 (t, 1H), 7.53-7.65 (m, 5H), 7.67 (s, 1H), 7.74(d, 2H), 8.69 (d, 1H).

Example 100 Ethyl{2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethyl}carbamate(diastereomer mixture)

Of the compound from Example 8A, 465 mg (1.27 mmol), 437 mg (1.40 mmol)of the compound from Example 137A, 292 mg (1.52 mmol) of EDC, 206 mg(1.52 mmol) of HOBt and 266 μl (1.52 mmol) of N,N-diisopropylethylaminewere stirred in 15 ml of DMF at RT for one hour. The entire solution waspurified by preparative HPLC [Method 23]. The appropriate fraction wasfreed from the solvents on a rotary evaporator and the residue was driedin an HV. This gave 524 mg (66% of theory) of the title compound as adiastereomer mixture (ratio 23:74).

LC-MS [Method 5] R_(t)=1.15 min; MS [ESIpos]: m/z=624 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 21a]: see Example 101 and Example 102.

Example 101 Ethyl{2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethyl}carbamate(diastereomer I)

First-eluting diastereomer (109 mg) from the chromatographic separationof 520 mg of the compound from Example 100 by Method 21a.

Chiral analytical HPLC [Method 22]: R_(t)=3.42 min

LC-MS [Method 5] R_(t)=1.15 min; MS [ESIpos]: m/z=624 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.08 (t, 3H), 3.23-3.40 (m, 2H), 3.79-3.99(m, 4H), 4.22-4.33 (m, 1H), 4.51 (s, 2H), 5.02 (q, 1H), 6.91 (d, 1H),7.21 (t, 1H), 7.53-7.68 (m, 6H), 7.75 (d, 2H), 8.68 (d, 1H).

Example 102 Ethyl{2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethyl}carbamate(diastereomer II)

Last-eluting diastereomer from the chromatographic separation of 520 mgof the compound from Example 100 by Method 21a. The resulting product(356 mg) was further purified by preparative HPLC [Method 20]. This gave297 mg of the title compound.

Chiral analytical HPLC [Method 22]: R_(t)=4.31 min

LC-MS [Method 5] R_(t)=1.15 min; MS [ESIpos]: m/z=624 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.08 (t, 3H), 3.23-3.37 (m, 2H), 3.28-4.01(m, 4H), 4.22-4.33 (m, 1H), 4.42-4.60 (m[AB], 2H), 5.01 (q, 1H), 6.88(d, 1H), 7.21 (t, 1H), 7.50-7.68 (m, 6H), 7.73 (d, 2H), 8.69 (d, 1H).

Example 1032-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(ethylcarbamoyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 483 mg (1.32 mmol), 453 mg (1.45 mmol)of the compound from Example 139A, 304 mg (1.59 mmol) of EDC, 214 mg(1.59 mmol) of HOBt and 276 μl (1.59 mmol) of N,N-diisopropylethylaminewere stirred in 15.5 ml of DMF at RT overnight. Since the reaction wasincomplete, 0.8 mmol each of EDC, HOBt and N,N-diisopropylethylaminewere added and the mixture was stirred further for 1 h. The entiresolution was purified by preparative HPLC [Method 23]. The appropriatefraction was freed from the solvents on a rotary evaporator and theresidue was dried in an HV. This gave 428 mg (52% of theory) of thetitle compound as a diastereomer mixture (ratio 3.5:1 according to NMR).

LC-MS [Method 4] R_(t)=1.09 min; MS [ESIpos]: m/z=623 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 13a]: see Example 104 and Example 105.

Example 1042-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(ethylcarbamoyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer (333 mg) from the chromatographic separationof 428 mg of the compound from Example 103 by Method 13a.

Chiral analytical HPLC [Method 14]: R_(t)=1.62 min

¹H NMR (400 MHz, DMSO-d₆): δ=0.92 (t, 3H), 2.88-3.00 (m, 2H), 3.21-3.39(m, 2H), 3.82 (dd, 1H), 3.97 (dd, 1H), 4.24-4.38 (m, 1H), 4.44-4.54(m[AB], 2H), 4.87-4.98 (m, 1H), 5.95 (q, 2H), 6.91 (d, 1H), 7.53-7.66(m, 6H), 7.76 (d, 2H), 8.79 (d, 1H).

Example 1052-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(ethylcarbamoyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer (100 mg) from the chromatographic separationof 428 mg of the compound from Example 103 by Method 13a.

Chiral analytical HPLC [Method 14]: R_(t)=2.60 min

¹H NMR (400 MHz, DMSO-d₆): δ=0.91 (t, 3H), 2.83-3.00 (m, 2H), 3.20-3.38(m, 2H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.27-4.39 (m, 1H), 4.41-4.51 (m[AB], 2H), 4.89-4.96 (m, 1H), 5.95 (q, 2H), 6.95 (d, 1H), 7.54-7.66 (m,6H), 7.77 (d, 2H), 8.79 (d, 1H).

Example 106N-[2-(Carbamoylamino)-1-(2-chlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 311 mg (0.85 mmol), 279 mg (0.94 mmol)of the compound from Example 143A, 245 mg (1.28 mmol) of EDC, 173 mg(1.28 mmol) of HOBt and 193 μl (1.11 mmol) of N,N-diisopropylethylaminewere stirred in 8 ml of DMF at RT for 2 h. The entire solution waspurified by preparative HPLC [Method 10]. The appropriate fraction wasfreed from the solvents on a rotary evaporator and the residue was driedin an HV. This gave 182 mg (36% of theory) of the title compound as adiastereomer mixture.

LC-MS [Method 4] R_(t)=0.97 and 0.98 min; MS [ESIpos]: m/z=561 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 17d]: see Example 107 and Example 108.

Example 107N-[2-(Carbamoylamino)-1-(2-chlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic separation of 120 mgof the compound from Example 106 by Method 17d. The resulting productwas further purified by preparative HPLC [Method 10]. This gave 40 mg ofthe title compound.

Chiral analytical HPLC [Method 18b]: R_(t)=1.81 min.

LC-MS [Method 3] R_(t)=1.12 min; MS [ESIpos]: m/z=561 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.15-3.25 (m, 1H), 3.26-3.36 (m, 1H), 3.84(dd, 1H), 3.98 (dd, 1H), 4.24-4.37 (m, 1H), 4.39-4.55 (m[AB], 2H),5.09-5.18 (m, 1H), 5.58 (s, 2H), 6.17 (t, 1H), 6.95 (d, 1H), 7.25-7.37(m, 2H), 7.39-7.45 (m, 2H), 7.63 (d, 2H), 7.77 (d, 2H), 8.81 (d, 1H).

Example 108N-[2-(Carbamoylamino)-1-(2-chlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic separation of 120 mgof the compound from Example 106 by Method 17d. The resulting product(51 mg) was further purified by preparative HPLC [Method 10]. This gave40 mg of the title compound.

Chiral analytical HPLC [Method 18b]: R_(t)=2.77 min.

LC-MS [Method 3] R_(t)=1.13 min; MS [ESIpos]: m/z=561 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.15-3.25 (m, 1H), 3.26-3.36 (m, 1H), 3.83(dd, 1H), 3.97 (dd, 1H), 4.26-4.38 (m, 1H), 4.42-4.53 (m [AB], 2H),5.09-5.17 (m, 1H), 5.59 (s, 2H), 6.18 (t, 1H), 6.95 (d, 1H), 7.25-7.37(m, 2H), 7.38-7.45 (m, 2H), 7.63 (d, 2H), 7.77 (d, 2H), 8.81 (d, 1H).

Example 1093-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propylcarbamate (diastereomer mixture)

Of the compound from Example 8A, 945 mg (2.59 mmol), 743 mg (3.88 mmol)of EDC and 552 mg (3.88 mmol) of HOBt were stirred in 25 ml of DMF at RTfor 20 min. The resulting solution was added dropwise to a solution of678 mg (2.59 mmol) of the compound from Example 129A in 75 ml ofacetonitrile. After 30 min at RT, the acetonitrile was removed on arotary evaporator. The remaining solution was admixed with 1 ml of 1Mhydrochloric acid and purified by preparative HPLC [Method 10]. Theappropriate fraction was freed from the solvents on a rotary evaporatorand the residue was dried in an HV. This gave 1.18 g (75% of theory) ofthe title compound.

LC-MS [Method 2] R_(t)=2.27 min; MS [ESIpos]: m/z=610 (M+H)⁺

The two diastereomers were separated from 180 mg of the resultingcompound by preparative HPLC on a chiral phase [Method 15a]: see Example110 and Example 111.

Example 1103-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propylcarbamate (diastereomer I)

First-eluting diastereomer from the separation of 180 mg of the compoundfrom Example 109 by Method 15a. The isolated product was furtherpurified by preparative HPLC [Method 10]. This gave 81 mg of the titlecompound.

Chiral analytical HPLC [Method 16]: R_(t)=2.40 min

LC-MS [Method 5] R_(t)=1.07 min; MS [ESIpos]: m/z=610 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.91-2.07 (m, 2H), 3.77-3.87 (m, 2H),3.88-3.99 (m, 2H), 4.22-4.35 (m, 1H), 4.50 (s, 2H), 4.95-5.04 (m, 1H),6.51 (br. s., 2H), 6.93 (d, 1H), 7.55-7.68 (m, 6H), 7.71-7.78 (m, 2H),8.78 (d, 1H).

Example 1113-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propylcarbamate (diastereomer II)

Last-eluting diastereomer from the separation of 180 mg of the compoundfrom Example 109 by Method 15a. The isolated product was furtherpurified by preparative HPLC [Method 10]. This gave 68 mg of the titlecompound.

Chiral analytical HPLC [Method 16]: R_(t)=3.28 min

LC-MS [Method 4] R_(t)=1.05 min; MS [ESIpos]: m/z=610(M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.90-2.07 (m, 2H), 3.76-4.03 (m, 4H),4.20-4.34 (m, 1H), 4.41-4.60 (m [AB], 2H), 4.93-5.05 (m, 1H), 6.52 (br.s., 2H), 6.91 (d, 1H), 7.55-7.68 (m, 6H), 7.74 (d, 2H), 8.79 (d, 1H).

Example 1122-({[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-[3-(trifluoromethyl)phenyl]ethylcarbamate (enantiomerically pure)

Of the compound from Example 65, 250 mg (0.43 mmol) were hydrogenated in37 ml of methanol in the presence of platinum (5% on carbon, 104 mg)under hydrogen (pressure=1 atm) at RT overnight. Subsequently thecatalyst was removed by filtration and the filtrate was purified bypreparative HPLC [Method 20]. This gave 161 mg (64% of theory) of thetitle compound.

LC-MS [Method 2] R_(t)=2.34 min; MS [ESIpos]: m/z=580 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.56-2.69 (m, 2H), 3.98 (t, 2H), 4.03-4.20(m, 2H), 4.43-4.59 (m [AB], 2H), 5.06-5.22 (m, 1H), 6.57 (br. s., 2H),7.55-7.75 (m, 8H), 8.85 (d, 1H).

Example 113 Methyl[2-({[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethyl]carbamate(racemate)

Of the compound from Example 177A, 144 mg (0.41 mmol), 136 mg (0.45mmol) of the compound from Example 151A, 94 mg (0.50 mmol) of EDC, 67 mg(0.50 mmol) of HOBt and 86 μl (0.50 mmol) of N,N-diisopropylethylaminewere stirred in 4.9 ml of DMF at RT for 1 h. The entire solution waspurified by preparative HPLC [Method 20]. The appropriate fraction wasfreed from the solvents on a rotary evaporator and the residue was driedin an HV. This gave 173 mg (70% of theory) of the title compound.

LC-MS [Method 5] R_(t)=1.15 min; MS [ESIpos]: m/z=594 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.54-2.68 (m, 2H), 3.21-3.36 (m, 2H), 3.50(s, 3H), 3.98 (t, 2H), 4.44-4.56 (m [AB], 2H), 5.31 (q, 1H), 7.31 (br.t, 1H), 7.36 (t, 1H), 7.45 (dd, 1H), 7.56 (dd, 1H), 7.61-7.69 (m, 4H),8.67 (d, 1H).

The two enantiomers were separated by preparative HPLC on a chiral phase[Method 21b]: see Example 114 and Example 115.

Example 114 Methyl[2-({[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethyl]carbamate(enantiomer 1)

First-eluting enantiomer (77 mg) from the chromatographic enantiomerseparation of 173 mg of the compound from Example 113 by Method 21b. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 62 mg of the title compound as a white solid.

Chiral analytical HPLC [Method 22]: R_(t)=6.48 min.

Example 115 Methyl[2-({[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethyl]carbamate(enantiomer 2)

Last-eluting enantiomer (71 mg) from the chromatographic enantiomerseparation of 173 mg of the compound from Example 113 by Method 21b. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 60 mg of the title compound as a white solid.

Chiral analytical HPLC [Method 22]: R_(t)=11.02 min.

Example 116 Ethyl[2-({[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethyl]carbamate(racemate)

Of the compound from Example 177A, 155 mg (0.44 mmol), 153 mg (0.49mmol) of the compound from Example 152A, 102 mg (0.53 mmol) of EDC, 72mg (0.53 mmol) of HOBt and 93 μl (0.53 mmol) ofN,N-diisopropylethylamine were stirred in 5 ml of DMF at RT for 1 h. Thereaction solution was purified by preparative HPLC [Method 20]. Theproduct fraction was freed from the solvents on a rotary evaporator andthe residue was dried in an HV. This gave 168 mg (62% of theory) of thetitle compound.

LC-MS [Method 5] R_(t)=1.20 min; MS [ESIpos]: m/z=608 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.11 (t, 3H), 2.53-2.69 (m, 2H), 3.21-3.35(m, 1H), 3.89-4.01 (m, 4H), 4.44-4.57 (m [AB], 2H), 5.31 (br. q, 1H),7.26 (br. t, 1H), 7.36 (t, 1H), 7.44 (dd, 1H), 7.55 (dd, 1H), 7.60-7.68(m, 4H), 8.67 (d, 1H).

The two enantiomers were separated by preparative HPLC on a chiral phase[Method 21b]: see Example 117 and Example 118.

Example 117 Ethyl[2-({[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethyl]carbamate(enantiomer 1)

First-eluting enantiomer (67 mg) from the chromatographic enantiomerseparation of 168 mg of the compound from Example 116 by Method 21b. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 54 mg of the title compound as a white solid.

Chiral analytical HPLC [Method 22]: R_(t)=5.36 min.

Example 118 Ethyl[2-({[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethyl]carbamate(enantiomer 2)

Last-eluting enantiomer (71 mg) from the chromatographic enantiomerseparation of 168 mg of the compound from Example 116 by Method 21b. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 60 mg of the title compound as a white solid.

Chiral analytical HPLC [Method 22]: R_(t)=9.85 min

Example 119N-[2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2-[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetamide(racemate)

Of the compound from Example 177A, 162 mg (0.46 mmol), 145 mg (0.51mmol) of the compound from Example 153A, 107 mg (0.56 mmol) of EDC, 75mg (0.56 mmol) of HOBt and 97 μl (0.56 mmol) ofN,N-diisopropylethylamine were stirred in 5.4 ml of DMF at RT overnight.The solution was diluted with 150 ml of ethyl acetate and extracted insuccession twice each with 1M hydrochloric acid and with 1M aqueoussodium hydrogen carbonate solution. The organic phase was dried oversodium sulphate and freed from the volatile components on a rotaryevaporator. The residue was purified by preparative HPLC [Method 20].The product fraction was freed from the solvents on a rotary evaporatorand the residue was dried in an HV. This gave 163 mg (61% of theory) ofthe title compound.

LC-MS [Method 5] R_(t)=1.04 min; MS [ESIpos]: m/z=579 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.56-2.72 (m, 2H), 3.17-3.37 (m, 2H), 3.98(t, 2H), 4.40-4.52 (m [AB], 2H), 5.11-5.18 (m, 1H), 5.56 (s, 2H), 6.14(t, 1H), 7.32-7.39 (m, 2H), 7.52-7.57 (m, 1H), 7.61-7.66 (m, 2H),7.66-7.71 (m, 2H), 8.93 (d, 1H).

The two enantiomers were separated by preparative HPLC on a chiral phase[Method 24a]: see Example 120 and Example 121.

Example 120N-[2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2-[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetamide(enantiomer 1)

First-eluting enantiomer (61 mg) from the chromatographic enantiomerseparation of 160 mg of the compound from Example 119 by Method 24a. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 34 mg of the title compound.

Chiral analytical HPLC [Method 25a]: R_(t)=4.28 min.

Example 121N-[2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2-[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetamide(enantiomer 2)

Last-eluting enantiomer (81 mg) from the chromatographic enantiomerseparation of 160 mg of the compound from Example 119 by Method 24a. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 39 mg of the title compound.

Chiral analytical HPLC [Method 25a]: R_(t)=9.50 min.

Example 1222-[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-(2,3-dichlorophenyl)-2-[(ethylcarbamoyl)amino]ethyl}acetamide(racemate)

Of the compound from Example 177A, 145 mg (0.42 mmol), 143 mg (0.46mmol) of the compound from Example 154A, 96 mg (0.50 mmol) of EDC, 67 mg(0.50 mmol) of HOBt and 87 μl (0.50 mmol) of N,N-diisopropylethylaminewere stirred in 4.9 ml of DMF at RT for 1 h. The entire solution waspurified by preparative HPLC [Method 20]. The product fraction was freedfrom the solvents on a rotary evaporator and the residue was dried in anHV. This gave 150 mg (58% of theory) of the title compound.

LC-MS [Method 5] R_(t)=1.12 min; MS [ESIpos]: m/z=607 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=0.92 (t, 3H), 2.57-2.71 (m, 2H), 2.86-2.99(m, 2H), 3.19-3.38 (m, 2H), 3.98 (t, 2H), 4.40-4.53 (m [AB], 2H),5.13-5.20 (m, 1H), 5.93 (t, 1H), 6.02 (t, 1H), 7.32-7.39 (m, 2H),7.50-7.58 (m, 1H), 7.61-7.72 (m, 4H), 8.91 (d, 1H).

The two enantiomers were separated by preparative HPLC on a chiral phase[Method 24b]: see Example 123 and Example 124.

Example 1232-[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-(2,3-dichlorophenyl)-2-[(ethylcarbamoyl)amino]ethyl}acetamide(enantiomer 1)

First-eluting enantiomer from the chromatographic enantiomer separationof 160 mg of the compound from Example 122 by Method 24b. The productobtained was further purified by preparative HPLC [Method 20]. Drying inan HV gave 55 mg of the title compound.

Chiral analytical HPLC [Method 25b]: R_(t)=4.69 min.

Example 1242-[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-(2,3-dichlorophenyl)-2-[(ethylcarbamoyl)amino]ethyl}acetamide(enantiomer 2)

Last-eluting enantiomer from the chromatographic enantiomer separationof 160 mg of the compound from Example 122 by Method 24b. The productobtained was further purified by preparative HPLC [Method 20]. Drying inan HV gave 51 mg of the title compound.

Chiral analytical HPLC [Method 25b]: R_(t)=9.41 min.

Example 125N-{1-(2-Chlorophenyl)-2-[(methylsulphonyl)amino]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 298 mg (0.81 mmol), 304 mg (0.90 mmol)of the compound from Example 144A, 234 mg (1.22 mmol) of EDC, 165 mg(1.22 mmol) of HOBt and 184 μl (1.06 mmol) of N,N-diisopropylethylaminewere stirred in 7.7 ml of DMF at RT for 2 h. The entire solution waspurified by preparative HPLC [Method 10]. The product fraction was freedfrom the solvents on a rotary evaporator and the residue was dried in anHV. This gave 448 mg (90% of theory) of the title compound.

LC-MS [Method 4] R_(t)=1.02 min; MS [ESIpos]: m/z=596 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 17h]: see Example 126 and Example 127.

Example 126N-{1-(2-Chlorophenyl)-2-[(methylsulphonyl)amino]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 440 mg of the compound from Example 125 by Method 17h. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 141 mg of the title compound.

Chiral analytical HPLC [Method 18e]: R_(t)=2.81 min

LC-MS [Method 4] R_(t)=1.01 min; MS [ESIpos]: m/z=596 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.87 (s, 3H), 3.11-3.20 (m, 1H), 3.25-3.35(m, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.22-4.34 (m, 1H), 4.46-4.64(m[AB], 2H), 5.31-5.39 (m, 1H), 6.85 (d, 1H), 7.28-7.40 (m, 3H), 7.44(d, 1H), 7.54 (d, 1H), 7.61 (d, 2H), 7.74 (d, 2H), 8.66 (d, 1H).

Example 127N-{1-(2-Chlorophenyl)-2-[(methylsulphonyl)amino]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic diastereomerseparation of 440 mg of the compound from Example 125 by Method 17h. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 102 mg of the title compound.

Chiral analytical HPLC [Method 18e]: R_(t)=4.14 min

LC-MS [Method 2] R_(t)=2.20 min; MS [ESIpos]: m/z=596 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.88 (s, 3H), 3.11-3.19 (m, 1H), 3.25-3.33(m, 1H), 3.83 (dd, 1H), 3.96 (br d, 1H), 4.23-4.34 (m, 1H), 4.55 (q,2H), 5.32-5.40 (m, 1H), 6.88 (d, 1H), 7.29-7.34 (br t, 2H), 7.37 (t,1H), 7.44 (d, 1H), 7.54 (d, 1H), 7.62 (d, 2H), 7.75 (d, 2H), 8.65 (d,1H).

Example 128N-{1-(2-Chlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 241 mg (0.66 mmol), 249 mg (0.74 mmol)of the compound from Example 145A, 189 mg (0.99 mmol) of EDC, 133 mg(0.99 mmol) of HOBt and 149 μl (0.99 mmol) of N,N-diisopropylethylaminewere stirred in 6.2 ml of DMF at RT for 2 h. The entire solution waspurified by preparative HPLC [Method 10]. The product fraction was freedfrom the solvents on a rotary evaporator and the residue was dried in anHV. This gave 375 mg (91% of theory) of the title compound.

LC-MS [Method 4] R_(t)=1.05 min; MS [ESIpos]: m/z=610 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 17g]: see Example 129 and Example 130.

Example 129N-{1-(2-Chlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 370 mg of the compound from Example 128 by Method 17g. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 96 mg of the title compound as a white solid.

Chiral analytical HPLC [Method 18d]: R_(t)=3.87 min

LC-MS [Method 4] R_(t)=1.04 min; MS [ESIpos]: m/z=610 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.15 (t, 3H), 2.88-3.02 (m, 2H), 3.11-3.19(m, 1H), 3.24-3.33 (m, 1H, hidden beneath water signal), 3.82 (dd, 1H),3.96 (dd, 1H), 4.22-4.33 (m, 1H), 4.49 (d, 1H), 4.60 (d, 1H), 5.28-5.37(m, 1H), 6.85 (d, 1H), 7.29-7.40 (m, 3H), 7.44 (d, 1H), 7.53 (d, 1H),7.61 (d, 2H), 7.74 (d, 2H), 8.64 (d, 1H).

Example 130N-{1-(2-Chlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic diastereomerseparation of 370 mg of the compound from Example 128 by Method 17g. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 134 mg of the title compound.

Chiral analytical HPLC [Method 18d]: R_(t)=5.08 min

LC-MS [Method 4] R_(t)=1.05 min; MS [ESIpos]: m/z=610(M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.16 (t, 3H), 2.90-3.02 (m, 2H), 3.10-3.19(m, 1H), 3.24-3.33 (m, 1H, hidden beneath water signal), 3.83 (dd, 1H),3.96 (br d, 1H), 4.23-4.34 (m, 1H), 4.48-4.61 (m [AB], 2H), 5.30-5.37(m, 1H), 6.88 (d, 1H), 7.28-7.39 (m, 3H), 7.43 (d, 1H), 7.53 (d, 1H),7.62 (d, 2H), 7.75 (d, 2H), 8.62 (d, 1H).

Example 131N-[1-(2-Chlorophenyl)-2-(methylsulphonyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 327 mg (0.89 mmol), 266 mg (0.98 mmol)of the compound from Example 146A, 206 mg (1.07 mmol) of EDC, 145 mg(1.07 mmol) of HOBt and 187 μl (1.07 mmol) of N,N-diisopropylethylaminewere stirred in 10.5 ml of DMF at RT for 1 h. The entire solution waspurified by preparative HPLC [Method 20]. The appropriate fraction wasfreed from the solvents on a rotary evaporator and the residue was driedin an HV. This gave 354 mg (68% of theory) of the title compound.

LC-MS [Method 3] R_(t)=1.16 min; MS [ESIpos]: m/z=581 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 26a]: see Example 132 and Example 133.

Example 132N-[1-(2-Chlorophenyl)-2-(methylsulphonyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 354 mg of the compound from Example 131 by Method 26a. Theproduct obtained (163 mg) was further purified by preparative HPLC[Method 20]. Drying in an HV gave 116 mg of the title compound.

Chiral analytical HPLC [Method 27a]: R_(t)=4.06 min

LC-MS [Method 5] R_(t)=1.03 min; MS [ESIpos]: m/z=581 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.02 (s, 3H), 3.42 (m, 1H), 3.62 (dd, 1H),3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.33 (m, 1H), 4.51 (s, 2H), 5.72-5.80(m, 1H), 6.89 (d, 1H), 7.31-7.42 (m, 2H), 7.47 (dd, 1H), 7.55 (dd, 1H),7.60-7.65 (m, 2H), 7.71-7.77 (m, 2H), 9.03 (d, 1H).

Example 133N-[1-(2-Chlorophenyl)-2-(methylsulphonyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic diastereomerseparation of 354 mg of the compound from Example 131 by Method 26a. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 131 mg of the title compound.

Chiral analytical HPLC [Method 27a]: R_(t)=4.71 min

LC-MS [Method 5] R_(t)=1.03 min; MS [ESIpos]: m/z=581 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.02 (s, 3H), 3.42 (m, 1H), 3.62 (dd, 1H),3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.35 (m, 1H), 4.46-4.57 (m [AB], 2H),5.74-5.81 (m, 1H), 6.91 (d, 1H), 7.31-7.42 (m, 2H), 7.46 (dd, 1H), 7.56(dd, 1H), 7.60-7.66 (m, 2H), 7.72-7.78 (m, 2H), 9.03 (d, 1H).

Example 1342-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphonyl)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 438 mg (1.20 mmol), 400 mg (1.32 mmol)of the compound from Example 148A, 275 mg (1.44 mmol) of EDC, 194 mg(1.44 mmol) of HOBt and 250 μl (1.44 mmol) of N,N-diisopropylethylaminewere stirred in 10.5 ml of DMF at RT for 1 h. The entire solution waspurified by preparative HPLC [Method 20]. The appropriate fraction wasfreed from the solvents on a rotary evaporator and the residue was driedin an HV. This gave 594 mg (79% of theory) of the title compound.

LC-MS [Method 3] R_(t)=1.19 min; MS [ESIpos]: m/z=615 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 11e]: see Example 135 and Example 136.

Example 1352-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphonyl)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer (245 mg) from the chromatographicdiastereomer separation of 594 mg of the compound from Example 134 byMethod 11e. The product obtained was admixed with 10 ml of acetonitrileand 20 ml of water and then lyophilized.

Chiral analytical HPLC [Method 12a]: R_(t)=5.11 min

LC-MS [Method 4] R_(t)=1.04 min; MS [ESIpos]: m/z=615 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.01 (s, 3H), 3.36 (dd, 1H), 3.67 (dd, 1H),3.82 (dd, 1H), 3.95 (dd, 1H), 4.21-4.33 (m, 1H), 4.48 (s, 2H), 5.74-5.84(m, 1H), 6.92 (d, 1H), 7.53 (t, 1H), 7.59-7.65 (m, 2H), 7.70-7.82 (m,5H), 9.08 (d, 1H).

Example 1362-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphonyl)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer (225 mg) from the chromatographic diastereomerseparation of 594 mg of the compound from Example 134 by Method 11e. Theproduct obtained was admixed with 10 ml of acetonitrile and 20 ml ofwater and then lyophilized.

Chiral analytical HPLC [Method 12a]: R_(t)=8.30 min

LC-MS [Method 4] R_(t)=1.03 min; MS [ESIpos]: m/z=615 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.01 (s, 3H), 3.36 (dd, 1H), 3.68 (dd, 1H),3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.31 (m, 1H), 4.44-4.53 (m[AB], 2H),5.73-5.82 (m, 1H), 6.89 (d, 1H), 7.53 (t, 1H), 7.59-7.64 (m, 2H),7.70-7.82 (m, 5H), 9.08 (d, 1H).

Example 1372-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphonyl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 416 mg (1.14 mmol), 380 mg (1.25 mmol)of the compound from Example 149A, 262 mg (1.37 mmol) of EDC, 184 mg(1.37 mmol) of HOBt and 238 μl (1.37 mmol) of N,N-diisopropylethylaminewere stirred in 13.4 ml of DMF at RT for 1 h. The entire solution waspurified by preparative HPLC [Method 23]. The appropriate fraction wasfreed from the solvents on a rotary evaporator and the residue was driedin an HV. This gave 458 mg (65% of theory) of the title compound.

LC-MS [Method 4] R_(t)=1.06 min; MS [ESIpos]: m/z=615 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 26b]: see Example 138 and Example 139.

Example 1382-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphonyl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 450 mg of the compound from Example 137 by Method 26b. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 151 mg of the title compound.

Chiral analytical HPLC [Method 27a]: R_(t)=3.61 min

LC-MS [Method 5] R_(t)=1.07 min; MS [ESIpos]: m/z=615 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.99 (s, 3H), 3.69 (d, 2H), 3.83 (dd, 1H),3.96 (dd, 1H), 4.21-4.31 (m, 1H), 4.45-4.55 (m [AB], 2H), 5.48 (q, 1H),6.89 (d, 1H), 7.57-7.80 (m, 8H), 8.99 (d, 1H).

Example 1392-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphonyl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic diastereomerseparation of 450 mg of the compound from Example 137 by Method 26b. Theproduct obtained was further purified by preparative HPLC [Method 20].Drying in an HV gave 145 mg of the title compound.

Chiral analytical HPLC [Method 27a]: R_(t)=4.40 min

LC-MS [Method 5] R_(t)=1.08 min; MS [ESIpos]: m/z=615 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.99 (s, 3H), 3.64-3.74 (m, 2H), 3.83 (dd,1H), 3.96 (dd, 1H), 4.22-4.34 (m, 1H), 4.44-4.56 (m [AB], 2H), 5.45-5.53(m, 1H), 6.91 (d, 1H), 7.57-7.80 (m, 8H), 8.98 (d, 1H).

Example 1402-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(dimethylsulphamoyl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 221 mg (0.60 mmol), 221 mg (0.66 mmol)of the compound from Example 150A, 174 mg (0.91 mmol) of EDC, 122 mg(0.91 mmol) of HOBt and 137 μl (0.79 mmol) of N,N-diisopropylethylaminewere stirred in 5.7 ml of DMF at RT for 2 h. The entire solution waspurified by preparative HPLC [Method 10]. The product fraction was freedfrom the solvents on a rotary evaporator and the residue was dried in anHV. This gave 337 mg (87% of theory) of the title compound.

LC-MS [Method 2] R_(t)=2.41 min; MS [ESIpos]: m/z=644 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 28]: see Example 141 and Example 142.

Example 1412-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(dimethylsulphamoyl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 337 mg of the compound from Example 140 by Method 28. Theproduct obtained (153 mg) was further purified by preparative HPLC[Method 20]. Drying in an HV gave 120 mg of the title compound.

Chiral analytical HPLC [Method 18d]: R_(t)=2.56 min

LC-MS [Method 5] R_(t)=1.13 min; MS [ESIpos]: m/z=644 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.75 (s, 6H), 3.48-3.63 (m, 2H), 3.83 (dd,1H), 3.97 (dd, 1H), 4.20-4.33 (m, 1H), 4.49 (s, 2H), 5.33-5.41 (m, 1H),6.90 (d, 1H), 7.58-7.79 (m, 8H), 8.92 (d, 1H).

Example 1422-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(dimethylsulphamoyl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic diastereomerseparation of 337 mg of the compound from Example 140 by Method 28. Theproduct obtained (160 mg) was further purified by preparative HPLC[Method 10]. Drying in an HV gave 129 mg of the title compound.

Chiral analytical HPLC [Method 18d]: R_(t)=2.56 min

LC-MS [Method 5] R_(t)=1.13 min; MS [ESIpos]: m/z=644 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.76 (s, 6H), 3.48-3.63 (m, 2H), 3.83 (dd,1H), 3.96 (dd, 1H), 4.21-4.34 (m, 1H), 4.42-4.55 (m [AB], 2H), 5.34-5.44(m, 1H), 6.92 (d, 1H), 7.58-7.79 (m, 8H), 8.91 (d, 1H).

Example 1432-[({3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[2-(trifluoromethyl)phenyl]ethylcarbamate (enantiomerically pure)

A solution of 135 mg (0.23 mmol) of the compound from Example 51 and 33mg (0.27 mmol) of DMAP in 1.6 ml of pyridine was admixed dropwise with95 μl (0.57 mmol) of trifluoromethanoic anhydride and the resultingmixture was stirred at RT for 3 days. Subsequently 2 ml of 1Nhydrochloric acid were added and the volatile components were removed ona rotary evaporator.

The residue was dissolved in a little DMSO and purified by preparativeHPLC [Method 10]. The product-containing fraction was freed from thesolvents on a rotary evaporator and the residue was dried in an HV. Thisgave 118 mg (90% of theory) of the title compound.

LC-MS [Method 4] R_(t)=1.13 min; MS [ESIpos]: m/z=578 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.98 (dd, 1H), 4.14 (dd, 1H), 4.48-4.58 (m[AB], 2H), 5.36-5.45 (m, 1H), 6.40-6.77 (br. s., 2H), 6.84 (dq, 1H),7.17 (dq, 1H), 7.52 (t, 1H), 7.61-7.76 (m, 7H), 8.98 (d, 1H).

Example 1442-({[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-[2-(trifluoromethyl)phenyl]ethylcarbamate (enantiomerically pure)

A solution of 118 mg (0.20 mmol) of the compound from Example 143 in 20ml of methanol was hydrogenated by means of a continuous-flowhydrogenation apparatus (H-Cube, Thales Nano, Budapest, Model HC-2-SS),equipped with a 5% Pt/C catalyst cartridge, at 45° C. with a flow rateof 1 ml/min under standard pressure. The methanol was removed on arotary evaporator and the residue was purified by preparative HPLC[Method 10]. This gave 31 mg (26% of theory) of the title compound.

LC-MS [Method 2] R_(t)=2.30 min; MS [ESIpos]: m/z=580 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.51-2.69 (m, 2H), 3.93-4.01 (m, 3H), 4.12(dd, 1H), 4.48 (s, 2H), 5.34-5.42 (m, 1H), 6.40-6.78 (br. s., 2H),7.49-7.55 (m, 1H), 7.60-7.76 (m, 7H), 8.94 (d, 1H).

Example 1452-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[2-(trifluoromethyl)phenyl]ethylethylcarbamate (diastereomerically pure)

Of the compound from Example 8A, 298 mg (0.81 mmol), 187 mg (0.98 mmol)of EDC and 132 mg (0.98 mmol) of HOBt were stirred in 5 ml of DMF for 10min. The resulting solution was added dropwise to a solution of 280 mg(0.90 mmol) of the compound from Example 187A and 156 μl (0.90 mmol) ofN,N-diisopropylethylamine in 10 ml of acetonitrile. The entire mixturewas left with stirring at RT for 20 min, then admixed with 3 ml of 1Nhydrochloric acid and purified by preparative chromatography [Method10]. The product fraction was freed from the solvents on a rotaryevaporator and the residue was dried in an HV. This gave 420 mg (83% oftheory) of the title compound.

LC-MS [Method 4] R_(t)=1.11 min; MS [ESIpos]: m/z=624 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=0.98 (t, 3H), 2.90-3.04 (m, 2H), 3.82 (dd,1H), 3.92-4.03 (m, 2H), 4.11-4.20 (m, 1H), 4.20-4.32 (m, 1H), 4.49 (s,2H), 5.35-5.44 (m, 1H), 6.88 (d, 1H), 7.20 (t, 1H), 7.53 (t, 1H),7.58-7.65 (m, 2H), 7.68-7.79 (m, 5H), 8.96 (d, 1H).

Example 1462-[({3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[2-(trifluoromethyl)phenyl]ethylethylcarbamate (enantiomerically pure)

A solution of 230 mg (0.37 mmol) of the compound from Example 145 and 54mg (0.44 mmol) of DMAP in 5 ml of pyridine was admixed dropwise with 155μl (0.92 mmol) of trifluoromethanoic anhydride and the resulting mixturewas stirred at RT overnight. Subsequently 2 ml of 1N hydrochloric acidwere added and the volatile components were removed on a rotaryevaporator. The residue was dissolved in a little DMSO and purified bypreparative HPLC [Method 10]. The product-containing fraction was freedfrom the solvents on a rotary evaporator and the residue was dried in anHV. This gave 168 mg (75% of theory) of the title compound.

LC-MS [Method 4] R_(t)=1.22 min; MS [ESIpos]: m/z=606 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=0.98 (t, 3H), 2.92-3.04 (m, 2H), 3.99 (dd,1H), 4.13-4.20 (m, 1H), 4.48-4.59 (m[AB], 2H), 5.37-5.45 (m, 1H), 6.85(dq, 1H), 7.17 (dq, 1H), 7.23 (t, 1H), 7.50-7.56 (m, 1H), 7.60-7.77 (m,7H), 8.99 (d, 1H).

Example 1472-({[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-[2-(trifluoromethyl)phenyl]ethylethylcarbamate (enantiomerically pure)

A solution of 168 mg (0.28 mmol) of the compound from Example 146 in 30ml of methanol was hydrogenated by means of a continuous-flowhydrogenation apparatus (H-Cube, Thales Nano, Budapest, Model HC-2-SS),equipped with a 5% Pt/C catalyst cartridge, at 70° C. with a flow rateof 1 ml/min under standard pressure. The methanol was removed on arotary evaporator and the residue was purified by preparative HPLC[Method 20]. This gave 96 mg (55% of theory) of the title compound.

LC-MS [Method 5] R_(t)=1.16 min; MS [ESIpos]: m/z=608 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=0.98 (t, 3H), 2.55-2.65 (m, 2H), 2.91-3.03(m, 2H), 3.94-4.02 (m, 3H), 4.10-4.19 (m, 1H), 4.47 (s, 2H), 5.35-5.43(m, 1H), 7.21 (t, 1H), 7.52 (t, 1H), 7.59-7.68 (m, 4H), 7.68-7.76 (m,3H), 8.94 (d, 1H).

Example 1482-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(2-oxo-1,3-oxazolidin-3-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 187 mg (0.51 mmol), 118 mg (0.61 mmol)of EDC and 87 mg (0.61 mmol) of HOBt were stirred in 5 ml of DMF for 5min. The resulting solution was added dropwise to a solution of 175 mg(0.56 mmol) of the compound from Example 140A and 89 μl (0.51 mmol) ofN,N-diisopropylethylamine in 5 ml of DMF. The entire mixture was stirredat RT for 2 h then admixed with 100 ml of 1N hydrochloric acid.Extraction was carried out with 500 ml of ethyl acetate. The organicphase was washed four times with water and once with saturated aqueoussodium chloride solution and then dried over sodium sulphate and freedfrom the volatile constituents on a rotary evaporator. The residue waspurified by preparative chromatography [Method 10]. The product fractionwas freed from the solvents on a rotary evaporator and the residue wasdried in an HV. This gave 265 mg (83% of theory) of the title compoundas a diastereomer mixture (ratio approximately 3:1 according to NMR,77:23 according to chiral HPLC [Method 27a]).

LC-MS [Method 4] R_(t)=1.09 min; MS [ESIpos]: m/z=622 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 26c]: see Example 149 and Example 150.

Example 1492-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(2-oxo-1,3-oxazolidin-3-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 265 mg of the compound from Example 148 by Method 26c. Theproduct obtained (192 mg) was further purified by preparative HPLC[Method 20]. Drying in an HV gave 126 mg of the title compound.

Chiral analytical HPLC [Method 27a]: R_(t)=3.75 min

LC-MS [Method 4]: R_(t)=1.09 min; MS [ESIpos]: m/z=622 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.42-3.52 (m, 3H), 3.57 (q, 1H), 3.83 (dd,1H), 3.97 (dd, 1H), 4.16 (t, 2H), 4.21-4.35 (m, 1H), 4.51 (s, 2H), 5.24(q, 1H), 6.89 (d, 1H), 7.57-7.64 (m, 3H), 7.64-7.69 (m, 1H), 7.69-7.78(m, 3H), 7.80 (s, 1H), 8.81 (d, 1H).

Example 1502-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(2-oxo-1,3-oxazolidin-3-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic diastereomerseparation of 265 mg of the compound from Example 148 by Method 26c.This gave 65 mg of the title compound in approximately 90% purity.

Chiral analytical HPLC [Method 27a]: R_(t)=6.01 min

LC-MS [Method 4] R_(t)=1.08 min; MS [ESIpos]: m/z=622 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.43-3.53 (m, 3H), 3.57 (q, 1H), 3.83 (dd,1H), 3.96 (dd, 1H), 4.17 (t, 2H), 4.22-4.33 (m, 1H), 4.43-4.58 (m, 2H),5.24 (q, 1H), 6.90 (d, 1H), 7.57-7.69 (m, 4H), 7.69-7.78 (m, 3H), 7.80(s, 1H), 8.80 (d, 1H).

Example 1512-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(2-oxoimidazolidin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 182 mg (0.50 mmol), 115 mg (0.60 mmol)of EDC and 85 mg (0.60 mmol) of HOBt were stirred in 5 ml of DMF for 5min. The resulting solution was added dropwise to a solution of 170 mg(0.55 mmol) of the compound from Example 141A and 87 μl (0.50 mmol) ofN,N-diisopropylethylamine in 5 ml of DMF. The entire mixture was stirredat RT for 2 h, then admixed with 100 ml of 1N hydrochloric acid.Extraction was carried out with 500 ml of ethyl acetate. The organicphase was washed four times with water and once with saturated aqueoussodium chloride solution, then dried over sodium sulphate and freed fromthe volatile constituents on a rotary evaporator. The residue waspurified by preparative chromatography [Method 10]. The product fractionwas freed from the solvents on a rotary evaporator and the residue wasdried in an HV. This gave 168 mg (54% of theory) of the title compoundas a diastereomer mixture (ratio 72:25 according to chiral HPLC [Method27a]).

LC-MS [Method 4] R_(t)=1.08 min; MS [ESIpos]: m/z=621 (M+H)⁺

The main diastereomer was isolated in pure form (see Example 152) bypreparative HPLC on a chiral phase [Method 26c]. The secondarydiastereomer (diastereomer 2) (R_(t) [Method 27a]=4.66 min) was notisolated.

Example 1522-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(2-oxoimidazolidin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 168 mg of the compound from Example 151 by Method 26a.Drying in an HV gave 107 mg of the title compound.

Chiral analytical HPLC [Method 27a]: R_(t)=3.87 min

LC-MS [Method 4] R_(t)=1.08 min; MS [ESIpos]: m/z=621 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.07-3.19 (m, 2H), 3.20-3.43 (m, 4H), 3.82(dd, 1H), 3.97 (m, 1H), 4.25-4.36 (m, 1H), 4.49 (s, 2H), 5.08-5.15 (m,1H), 6.37 (s, 1H), 6.90 (d, 1H), 7.56-7.70 (m, 5H), 7.72-7.78 (m, 3H),8.70 (d, 1H).

Example 153N-[1-(2-Chlorophenyl)-2-(methylsulphanyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 53 mg (0.14 mmol), 38 mg (0.16 mmol) ofthe compound from Example 147A, 33 mg (0.17 mmol) of EDC, 24 mg (0.17mmol) of HOBt and 30 μl (0.17 mmol) of N,N-diisopropylethylamine werestirred in 1.7 ml of DMF at RT for 1 h. The solution was then acidifiedwith 1N hydrochloric acid and the entire solution was purified bypreparative HPLC [Method 20]. The product fraction was freed from thesolvents on a rotary evaporator and the residue was dried in an HV. Thisgave 70 mg of the title compound (87% of theory).

LC-MS [Method 5] R_(t)=1.16 min; MS [ESIpos]: m/z=549 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.09 (2s, 1s per diastereomer, 3H),2.71-2.85 (m, 2H), 3.83 (dd, 1H), 3.96 (br d, 1H), 4.20-4.33 (m, 1H),4.47-4.58 (m, 2H), 5.35-5.44 (m, 1H), 6.87-6.92 (m, interpreted as 1dper diastereomer, (6.89+6.90), 1H), 7.27-7.40 (m, 2H), 7.43 (br d, 1H),7.52 (br d, 1H), 7.63 (2d, 2H), 7.74 (d, 2H), 8.82 (d, 1H).

Example 1542-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphanyl)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 303 mg (0.83 mmol), 248 mg (0.91 mmol)of the compound from Example 142A, 191 mg (1.00 mmol) of EDC, 135 mg(1.00 mmol) of HOBt and 173 μl (1.00 mmol) of N,N-diisopropylethylaminewere stirred in 9.8 ml of DMF at RT for 1 h. The entire solution waspurified by preparative HPLC [Method 20]. The appropriate fraction wasfreed from the solvents on a rotary evaporator and the residue was driedin an HV. This gave 362 mg (73% of theory) of the title compound.

LC-MS [Method 3] R_(t)=1.33 min; MS [ESIpos]: m/z=583 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 29]: see Example 155 and Example 156.

Example 1552-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphanyl)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 360 mg of the compound from Example 154 by Method 29. Theresulting product (148 mg) was further purified by preparative HPLC[Method 20]. Drying in an HV gave 119 mg of the title compound.

Chiral analytical HPLC [Method 30]: R_(t)=4.40 min

LC-MS [Method 31] R_(t)=2.53 min; MS [ESIpos]: m/z=583 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.06 (s, 3H), 2.74-2.83 (m, 2H), 3.82 (dd,1H), 3.95 (dd, 1H), 4.20-4.34 (m, 1H), 4.44-4.55 (m [AB], 2H), 5.32-5.41(m, 1H), 6.92 (d, 1H), 7.50 (t, 1H), 7.60-7.65 (m, 2H), 7.67-7.78 (m,5H), 8.86 (d, 1H).

Example 1562-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphanyl)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic diastereomerseparation of 360 mg of the compound from Example 154 by Method 29. Theresulting product (157 mg) was further purified by preparative HPLC[Method 20]. Drying in an HV gave 108 mg of the title compound.

Chiral analytical HPLC [Method 30]: R_(t)=5.97 min

LC-MS [Method 31] R_(t)=2.54 min; MS [ESIpos]: m/z=583 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.06 (s, 3H), 2.73-2.84 (m, 2H), 3.82 (dd,1H), 3.96 (dd, 1H), 4.20-4.32 (m, 1H), 4.43-4.56 (m [AB], 2H), 5.36 (q,1H), 6.90 (d, 1H), 7.51 (t, 1H), 7.59-7.65 (m, 2H), 7.68-7.78 (m, 5H),8.87 (d, 1H).

Example 1572-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-[3-(difluoromethyl)phenyl]-2-hydroxyethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 53 mg (0.14 mmol), 39 mg (0.17 mmol) ofthe compound from Example 155A, 33 mg (0.17 mmol) of EDC, 24 mg (0.17mmol) of HOBt and 30 μl (0.17 mmol) of N,N-diisopropylethylamine werestirred in 1.7 ml of DMF at RT overnight. On account of the partialesterification of the product with reactant 8A, 0.5 ml of 1N aqueouslithium hydroxide solution was added, and the mixture was stirred for 1h. It was subsequently acidified with 1N hydrochloric acid and theentire solution was purified by preparative HPLC [Method 20]. Theproduct fraction was freed from the solvents on a rotary evaporator andthe residue was dried in an HV. This gave 362 mg (73% of theory) of thetitle compound.

LC-MS [Method 5] R_(t)=1.01 min; MS [ESIpos]: m/z=535 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.61 (t, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H),4.21-4.33 (m, 1H), 4.47-4.59 (m, 2H), 4.86-4.95 (m, 1H), 4.98 (t, 1H),6.89 (t, 1H interpreted as 1d per diastereomer), 7.00 (dt, J=3Hz, 56 Hz,1H), 7.42-7.55 (m, 4H), 7.59-7.66 (m, 2H), 7.74 (dd, 2H, interpreted as1d per diastereomer), 8.66 (dd, 1H, interpreted as 1d per diastereomer).

Example 1583-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propylsulphamate (diastereomer mixture)

A solution of 27 mg (48 μmol) of the compound from Example 66 in 0.5 mlof dry DMF and 100 μl of triethylamine was admixed slowly dropwise witha solution of 83 mg of sulphamyl chloride in 2 ml of DMF. When areaction check showed only 20% conversion, a further 200 mg of sulphamylchloride in solid form were added. After 10 min, 2 ml of 1N hydrochloricacid were added and the entire reaction mixture was purified bypreparative HPLC [Method 10]. The product fraction was freed from thevolatile components on a rotary evaporator and the residue was dried inan HV. This gave 12 mg (36% of theory) of the title compound inapproximately 92% purity.

LC-MS [Method 3] R_(t)=1.25 and 1.26 min; MS [ESIpos]: m/z=646 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.12 (q, 2H), 3.82 (dd, 1H), 3.92-4.04 (m,2H), 4.04-4.13 (m, 1H), 4.22-4.32 (m, 1H), 4.44-4.59 (m, 2H), 4.98-5.07(m, 1H), 6.91 (t, 1H interpreted as 1d per diastereomer), 7.48 (s, 2H),7.56-7.78 (m, 9H), 8.84 (dd, 1H, interpreted as 1d per diastereomer).

Example 1592-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethylsulphamate (diastereomer mixture)

Of the compound from Example 8A, 187 mg (0.51 mmol), 200 mg(approximately 90% pure, 0.56 mmol) of the compound from Example 157A,117 mg (0.61 mmol) of EDC, 83 mg (0.61 mmol) of HOBt and 107 μl (0.61mmol) of N,N-diisopropylethylamine were stirred in 5.9 ml of DMF at RTfor 1 h. The solution was subsequently acidified with 1N hydrochloricacid and the entire solution was purified by preparative HPLC [Method10]. The product fraction was freed from the solvents on a rotaryevaporator and the residue was dried in an HV. This gave 215 mg (60% oftheory) of the title compound in approximately 90% purity.

LC-MS [Method 3] R_(t)=1.26 and 1.27 min; MS [ESIpos]: m/z=632 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.83 (dd, 1H), 3.97 (br d, 1H), 4.18-4.34(m, 3H), 4.51-4.63 (m, 2H), 5.28-5.35 (m, 1H), 6.91 (t (interpreted as1d per diastereomer, 1H), 7.53-7.83 (m, 10H), 8.95+8.97 (1d perdiastereomer, 1H).

Example 160N-[2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(enantiomerically pure)

In the same way as for Example 146, from 110 mg (185 μmol) of thecompound from Example 62, the title compound was obtained (22 mg, 21% oftheory).

LC-MS [Method 3] R_(t)=1.28 min; MS [ESIpos]: m/z=577 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.19-3.38 (m, 2H), 4.45-4.60 (m, 2H),5.14-5.23 (m, 1H), 5.54 (s, 2H), 6.14 (t, 1H), 6.85 (dq, 1H), 7.19 (dq,1H), 7.33-7.42 (m, 2H), 7.55 (dd, 1H), 7.63-7.71 (m, 4H), 8.99 (d, 1H).

Example 161N-{2-(Carbamoylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(enantiomerically pure)

In the same way as for Example 146, from 87 mg (146 μmol) of thecompound from Example 57, the title compound was obtained (15 mg, 18% oftheory).

LC-MS [Method 4] R_(t)=1.09 min; MS [ESIpos]: m/z=577 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.18-3.40 (m, 2H), 4.46-4.60 (m, 2H),4.89-4.97 (m, 1H), 5.55 (s, 2H), 6.05 (t, 1H), 6.86 (dq, 1H), 7.19 (dq,1H), 7.54-7.69 (m, 8H), 8.86 (d, 1H).

Example 1622-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(sulphamoylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 62.2 mg (0.17 mmol), 53 mg (0.19 mmol)of the compound from Example 134A, 39 mg (0.20 mmol) of EDC and 20 mg(0.20 mmol) of HOBt were stirred in 2 ml of DMF at RT overnight.Subsequently 1 ml of 1N hydrochloric acid was added and the entiresolution was purified by preparative HPLC [Method 20]. The productfraction was freed from the solvents on a rotary evaporator and theresidue was dried in an HV. This gave 84 mg of the title compound (78%of theory).

LC-MS [Method 5] R_(t)=1.03 min; MS [ESIpos]: m/z=631 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.20 (br. t, 1H), 3.82 (dd, 1H), 3.96 (dt,interpreted as 1 dd per diastereomer, 1H), 4.21-4.34 (m., 1H), 4.45-4.62(m, 2H), 5.05-5.14 (m, 1H,) 6.61-6.65 (m, 2H), 6.70-6.78 (m, 1H), 6.91(dd, interpreted as 1d per diastereomer, 2H), 7.56-7.64 (m, 5H), 7.70(br.s, 1H), 7.74-7.78 (m, 2H), 8.62-8.70 (t, 1H, interpreted as 1d perdiastereomer).

Example 1632-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}-N-methylacetamide(diastereomer mixture)

Of the compound from Example 8A, 1.87 g (5.12 mmol), 1.18 mg (6.14 mmol)of EDC and 874 mg (6.14 mmol) of HOBt were stirred in 100 ml of DMF for5 min. The resulting solution was added dropwise to a solution of 1.44 g(5.63 mmol) of the compound from Example 156A and 892 μl (5.12 mmol) ofN,N-diisopropylethylamine in 50 ml of DMF. The entire mixture was leftwith stirring at RT for 1 h, then admixed with 100 ml of 1N hydrochloricacid. Extraction was carried out with 500 ml of ethyl acetate. Theorganic phase was washed four times with water and once with saturatedaqueous sodium chloride solution, then dried over sodium sulphate andfreed from the volatile constituents on a rotary evaporator. The residuewas purified by preparative chromatography (Method 20 and then again byMethod 32). The product fraction was freed from the solvents on a rotaryevaporator and the residue was dried in an HV. This gave 637 mg (22% oftheory) of the title compound as a diastereomer mixture.

LC-MS [Method 4] R_(t)=1.08 min; MS [ESIpos]: m/z=567 (M+H)⁺

The two diastereomers were separated by preparative HPLC on a chiralphase [Method 26d]: see Example 164 and Example 165.

Example 1642-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}-N-methylacetamide(diastereomer I)

First-eluting diastereomer from the chromatographic diastereomerseparation of 200 mg of the compound from Example 163 by Method 26d. Theproduct obtained (93 mg) was further purified by preparative HPLC[Method 20]. Drying in an HV gave 80 mg of the title compound.

Chiral analytical HPLC [Method 27b]: R_(t)=4.82 min

LC-MS [Method 4] R_(t)=1.08 min; MS [ESIpos]: m/z=567 (M+H)⁺

NMR shows two rotamers, A and B, in a ratio of about 2:1:

¹H NMR (400 MHz, DMSO-d₆): δ=2.64 (s, 3H_(B)), 2.94 (s, 3H_(A)),3.77-4.04 (m, 4H), 4.21-4.33 (m, 1H), 4.78 (d, 1H_(A)), 4.90 (d,1H_(B)), 4.91 (d, 1H_(A)), 5.00 (d, 1H_(B)), 5.05 (t, 1H_(A)), 5.18-5.25(m, 1H_(B)), 5.28-5.33 (m, 1H_(B)), 5.57 (t, 1H_(A)), 6.89 (d, 1H_(A)),6.92 (d, 1H_(B)), 7.55-7.72 (m, 6H), 7.76 (d, 2H).

Example 1652-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}-N-methylacetamide(diastereomer II)

Last-eluting diastereomer from the chromatographic diastereomerseparation of 200 mg of the compound from Example 163 by Method 26d. Theproduct obtained (96 mg) was further purified by preparative HPLC[Method 20]. Drying in an HV gave 63 mg of the title compound.

Chiral analytical HPLC [Method 27b]: R_(t)=6.60 min

LC-MS [Method 4] R_(t)=2.54 min; MS [ESIpos]: m/z=567 (M+H)⁺

NMR (in D6-DMSO) shows two rotamers, A and B, in a ratio of about 2:1:

¹H NMR (400 MHz, DMSO-d₆): δ=2.63 (s, 3H_(B)), 2.94 (s, 3H_(A)),3.81-4.03 (m, 4H), 4.21-4.33 (m, 1H), 4.78 (d, 1H_(A)), 4.91 (d,1H_(A)), 4.90-5.03 (m [AB], 2H_(B)), 5.05 (t, 1H_(A)), 5.21 (t, 1H_(B)),5.31 (t, 1H_(B)), 5.57 (t, 1H_(A)), 6.89 (d, 1H_(b)), 6.91 (d, 1H_(A)),7.55-7.73 (m, 6H), 7.758 (d, 2H_(B)), 7.764 (d, 2H_(A)).

Example 166N-[1-(3-Chloro-2-fluorophenyl)-2-hydroxyethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide(diastereomer mixture)

Of the compound from Example 8A, 150 mg (0.39 mmol) were dissolved in 1ml of DMF, admixed with 87 mg (0.51 mmol) of EDC and with 68 mg (0.51mmol) of HOBt and stirred subsequently at room temperature for 20minutes. Then 115 mg (0.43 mmol) of the compound from Example 161A andalso 60 μl (0.43 mmol) of triethylamine were added and the mixture wasleft with stirring at room temperature for 16 h. For work-up, 100 μl of1N hydrochloric acid were added and the crude product was purifieddirectly by preparative HPLC [Method 19]. This gave 171 mg (82% oftheory) of the target compound as a diastereomer mixture.

LC-MS [Method 3] R_(t)=1.18 and 1.19 min; MS [ESIpos]: m/z=537 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ=3.24 and 3.48 (2m, 1H), 3.58-3.68 (m, 1H),3.73-3.81 (2m, 1H), 3.83-4.16 (m, 3H), 4.47-4.77 (m, 3H), 5.28 and 5.62(2d, 1H), 5.27-5.37 (m, 1H), 6.98 and 7.56 (2d, 1H), 7.01-7.10 (m, 1H),7.12-7.22 (m, 1H), 7.29-7.37 (m, 1H), 7.46 and 7.49 (2d, 2H), 7.62 and7.68 (2d, 2H). (Partial resolution of the two-fold set of signals of thediastereomer mixture).

The following compounds were obtained analogously:

¹H-NMR Reactant; (400 MHz) Example Yield LC/MS: No. Structure [% oftheory] R_(t) [Method] 167

8A; 162A 76% (CDCl₃): δ = 3.93-4.19 (m, 3H), 4.36-4.84 (m, 4H),4.84-5.00 (m, 2H), 5.36-5.48 (m, 1H), 5.74 and 6.04 (d, 1H), 7.06 and7.61 (d, 1H), 7.08-7.24 (m, 2H), 7.30-7.40 (m, 1H), 7.53 (d, 2H), 7.70-7.79 (m, 2H). R_(t) = 1.04 min; MS [ESIpos]: m/z = 580 (M + H)⁺ [5] 168

WO2007/134862 Example 218A; 161A 48% (DMSO-d₆): δ = 3.60 (t, 2H),4.33-4.40 (m, 2H), 4.48-4.58 (m, 2H), 4.95 (dd, 1H), 5.07- 5.17 (m, 3H),5.78- 5.91 (m, 1H), 7.18-7.25 (m, 1H), 7.35-7.41 (m, 1H), 7.45-7.52 (m,1H), 7.55-7.68 (m, 4H), 8.74 (d, 1H). R_(t) = 1.00 min; MS [ESIpos]: m/z= 467 (M + H)⁺ [4] 169

WO2007/134862 Example 102A; 161A 69% (DMSO-d₆): δ = 0.85 (d, 6H), 1.96(spt, 1H), 3.60 (t, 2H), 3.80 (d, 2H), 4.49-4.61 (m, 2H), 5.07- 5.18 (m,2H), 7.23 (t, 1H), 7.36-7.53 (m, 4H), 7.94-8.06 (m, 3H), 8.75 (d, 1H).R_(t) = 1.13 min; MS [ESIpos]: m/z = 503 (M + H)+ [5] 170

WO2007/134862 Example 92A; 161A 53% (DMSO-d₆): δ = 0.47- 0.53 (m, 2H),0.70-0.77 (m, 2H), 2.88-2.96 (m, 1H), 3.59 (t, 2H), 4.42- 4.52 (m, 2H),5.05-5.15 (m, 2H), 7.19 (t, 1H), 7.33-7.51 (m, 4H), 7.54- 7.67 (m, 2H),8.69 (d, 1H). R_(t) = 1.03 min; MS [ESIpos]: m/z = 449 (M + H)⁺ [3] 171

166A; 161A 13% (DMSO-d₆): δ = 3.59 (t, 2H), 4.06-4.12 (m, 2H), 4.49-4.58(m, 2H), 4.86 (d, 1H), 5.01 (d, 1H), 5.08-5.17 (m, 2H), 5.60-5.71 (m,1H), 7.21 (t, 1H), 7.34- 7.41 (m, 1H), 7.45-7.53 (m, 2H), 7.62 (dd, 1H),7.99 (d, 1H), 8.70 (d, 1H). R_(t) = 1.05 min; MS [ESIpos]: m/z = 543(M + H)⁺ [4] 172

WO2007/134862 Example 249A; 161A 53% (DMSO-d₆): δ = 0.71 (d, 6H), 1.77(spt, 1H), 2.22 (s, 3H), 3.37-3.48 (m, 2H), 3.59 (t, 2H), 4.48- 4.58 (m,2H), 5.07-5.15 (m, 2H), 7.21 (t, 1H), 7.33-7.40 (m, 1H), 7.45- 7.52 (m,1H), 7.70 (d, 1H), 8.73 (d, 1H). R_(t) = 2.26 min; MS [ESIpos]: m/z =503 and 505 (M + H)⁺ [2] 173

WO2007/134862 Example 101A; 161A 55% (DMSO-d₆): δ = 0.76 (d, 6H), 1.78(spt, 1H), 3.59 (t, 2H), 3.66 (d, 2H), 4.43-4.54 (m, 2H), 5.06- 5.16 (m,2H), 7.21 (t, 1H), 7.35-7.40 (m, 1H), 7.42 (dd, 1H), 7.45- 7.51 (m, 1H),7.72 (dd, 1H), 8.02 (dd, 1H), 8.69 (d, 1H). R_(t) = 1.11 min; MS[ESIpos]: m/z = 453 (M + H)⁺ [3] 174

WO2007/134862 Example 154A; 161A 65% (DMSO-d₆): δ = 3.56- 3.64 (m, 2H),4.51-4.61 (m, 2H), 5.08-5.18 (m, 4H), 7.00-7.06 (m, 1H), 7.12-7.26 (m,5H), 7.31-7.42 (m, 2H), 7.46-7.52 (m, 1H), 8.78 (d, 1H). R_(t) = 1.10min; MS [ESIpos]: m/z = 538 and 540 (M + H)⁺ [4] 175

WO2007/134862 Example 97A; 161A 37% (DMSO-d₆): δ = 3.30 (s, 3H), 3.60(t, 2H), 4.50 (s, 2H), 5.06-5.17 (m, 2H), 7.21 (t, 1H), 7.35- 7.41 (m,1H), 7.45-7.52 (m, 1H), 7.57-7.64 (m, 2H), 7.71 (d, 2H), 8.71 (d, 1H).R_(t) = 1.99 min; MS [ESIpos]: m/z = 439 and 441 (M + H)⁺ [2] 176

170A; 161A 76% (DMSO-d₆): δ = 3.19 (s, 3H), 3.54 (t, 2H), 3.59 (t, 2H),3.96 (t, 2H), 4.44-4.54 (m, 2H), 5.08- 5.15 (m, 2H), 7.22 (t, 1H), 7.26(d, 1H), 7.33- 7.41 (m, 1H), 7.45-7.52 (m, 1H), 7.56 (d, 1H), 8.74 (d,1H). R_(t) = 2.08 min; MS [ESIpos]: m/z = 489 and 491 (M + H)⁺ [2] 177

WO2007/134862 Example 99A; 161A 50% (DMSO-d₆): δ = 0.81 (d, 6H), 1.87(spt, 1H), 3.59 (t, 2H), 3.68 (d, 2H), 4.44-4.55 (m, 2H), 5.05- 5.16 (m,2H), 7.18- 7.26 (m, 2H), 7.34-7.42 (m, 1H), 7.44-7.51 (m, 1H), 7.57 (d,1H), 7.77 (d, 1H), 8.71 (d, 1H). R_(t) = 0.99 min; MS [ESIpos]: m/z =453 (M + H)⁺ [5] 178

WO2007/134862 Example 100A; 161A 67% (DMSO-d₆): δ = 0.81 (d, 6H), 1.87(spt, 1H), 3.59 (t, 2H), 3.67 (d, 2H), 4.44-4.55 (m, 2H), 5.07- 5.16 (m,2H), 7.18- 7.24 (m, 1H), 7.26 (d, 1H), 7.34-7.41 (m, 1H), 7.44-7.53 (m,2H), 8.73 (d, 1H). R_(t) = 1.08 min; MS [ESIpos]: m/z = 487 and 489 (M +H)⁺ [4] 179

WO2007/134862 Example 89A; 161A 62% (DMSO-d₆): δ = 0.66 (d, 6H), 1.66(spt, 1H), 3.29 (d, 1H), 3.59 (t, 2H), 4.47-4.57 (m, 2H), 5.07- 5.16 (m,2H), 7.17- 7.23 (m, 1H), 7.34-7.40 (m, 1H), 7.44-7.57 (m, 3H), 7.58-7.65(m, 1H), 7.65-7.70 (m, 1H), 8.69 (d, 1H). R_(t) = 1.04 min; MS [ESIpos]:m/z = 481 and 483 (M + H)⁺ [5] 180

WO2007/134862 Example 156A; 161A 63% (DMSO-d₆): δ = 3.60 (t, 2H),4.51-4.62 (m, 2H), 5.02 (s, 2H), 5.09- 5.19 (m, 2H), 7.01-7.25 (m, 5H),7.26-7.34 (m, 1H), 7.36-7.43 (m, 1H), 7.46-7.55 (m, 4H), 8.77 (d, 1H).R_(t) = 1.09 min; MS [ESIpos]: m/z = 533 and 535 (M + H)⁺ [4] 181

WO2007/134862 Example 220A; 161A 62% (DMSO-d₆): δ = 0.62 (s, 9H), 3.59(t, 2H), 3.67 (s, 2H), 4.47-4.57 (m, 2H), 5.08-5.16 (m, 2H), 7.20 (t,1H), 7.34- 7.40 (m, 1H), 7.45-7.51 (m, 1H), 7.58 (d, 2H), 7.65 (d, 2H),8.71 (d, 1H). R_(t) = 1.11 min; MS [ESIpos]: m/z = 495 (M + H)⁺ [4] 182

WO2007/134862 Example 91A, 161A 71% (DMSO-d₆): δ = 0.66- 0.80 (m, 2H),0.91-1.09 (m, 3H), 1.33-1.61 (m, 6H), 3.55-3.66 (m, 4H), 4.45-4.56 (m,2H), 5.07-5.16 (m, 2H), 7.20 (t, 1H), 7.34- 7.40 (m, 1H), 7.44-7.52 (m,1H), 7.60 (d, 2H), 7.66 (d, 2H), 8.72 (d, 1H). R_(t) = 1.36 min; MS[ESIpos]: m/z = 521 and 523 (M + H)⁺ [3] 183

166A; 92A 48% (DMSO-d₆): δ = 3.60 (t, 2H), 4.10 (d, 2H), 4.48- 4.59 (m,2H), 4.86 (d, 1H), 5.01 (d, 1H), 5.07- 5.19 (m, 2H), 5.60-5.71 (m, 1H),7.13-7.26 (m, 2H), 7.32 (q, 1H), 7.50 (d, 1H), 7.62 (dd, 1H), 7.98 (d,1H), 8.67 (d, 1H). R_(t) = 1.16 min; MS [ESIpos]: m/z = 529 (M + H)⁺ [3]184

WO2007/134862 Example 156A; 92A 70% (DMSO-d₆): δ = 3.60 (t, 2H),4.51-4.61 (m, 2H), 5.02 (s, 2H), 5.10 (t, 1H), 5.13-5.19 (m, 1H),7.01-7.26 (m, 5H), 7.27-7.37 (m, 2H), 7.52 (s, 4H), 8.74 (d, 1H). R_(t)= 1.21 min; MS [ESIpos]: m/z = 517 (M + H)⁺ [3] 185

WO2007/134862 Example 154A; 92A 70% (DMSO-d₆): δ = 3.60 (t, 2H),4.51-4.61 (m, 2H), 5.08-5.20 (m, 4H), 7.04 (t, 1H), 7.12- 7.27 (m, 6H),7.28-7.39 (m, 2H), 8.75 (d, 1H). R_(t) = 1.22 min; MS [ESIpos]: m/z =523 (M + H)⁺ [3] 186

WO2007/134862 Example 218A, 92A 70% (DMSO-d₆): δ = 3.60 (t, 2H),4.34-4.39 (m, 2H), 4.48-4.58 (m, 2H), 4.95 (d, 1H), 5.06- 5.19 (m, 3H),5.79-5.91 (m, 1H), 7.15-7.26 (m, 2H), 7.28-7.36 (m, 1H), 7.55-7.68 (m,4H), 8.71 (d, 1H). R_(t) = 0.96 min; MS [ESIpos]: m/z = 449 (M + H)⁺ [4]

Example 1872-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-[3-hydroxy-1-(2-methoxyphenyl)propyl]acetamide(diastereomer mixture)

Of the compound from Example 8A, 134 mg (0.37 mmol) were dissolved in 1ml of DMF, admixed with 106 mg (0.55 mmol) of EDC and with 74 mg (0.55mmol) of HOBt and subsequently stirred at room temperature for 20minutes. Then 88 mg (0.40 mmol) of the compound from Example 172A and 85μl (0.51 mmol) of N,N-diisopropylethylamine were added and the mixturewas left with stirring at room temperature for 16 h. For work-up, 100 μlof 1N hydrochloric acid were added and the crude product was purifieddirectly by preparative HPLC [Method 19]. This gave 77 mg (40% oftheory) of the target compound as a diastereomer mixture.

LC-MS [Method 4] R_(t)=0.99 min; MS [ESIpos]: m/z=529 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.70-1.87 (m, 2H), 3.35-3.45 (m, 2H), 3.78(s, 3H), 3.80-3.86 (m, 1H), 3.92-4.01 (m, 1H), 4.22-4.33 (m, 1H),4.40-4.56 (m, 3H), 5.16-5.26 (m, 1H), 6.86-6.99 (m, 3H), 7.16-7.31 (m,2H), 7.59-7.68 (m, 2H), 7.71-7.79 (m, 2H), 8.42 (d, 1H). (partialresolution of the two-fold set of signals of the diastereomer mixture).

Example 1883-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-(2-methoxyphenyl)propylcarbamate (diastereomer mixture)

Of the compound from Example 8A, 237 mg (0.65 mmol) were dissolved in 2ml of DMF, admixed with 174 mg (0.91 mmol) of EDC and with 123 mg (0.91mmol) of HOBt and subsequently stirred at room temperature for 20minutes. Then 186 mg (0.71 mmol) of the compound from Example 174A and129 μl (0.78 mmol) of N,N-diisopropylethylamine were added and themixture was left with stirring at room temperature for 16 h. Forwork-up, 100 μl of 1N hydrochloric acid were added and the crude productwas purified directly by preparative HPLC [Method 19]. This gave 123 mg(33% of theory) of the target compound as a diastereomer mixture.

LC-MS [Method 5] R_(t)=1.01 min; MS [ESIpos]: m/z=572 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.71-1.99 (m, 2H), 3.78 (s, 3H), 3.80-4.00(m, 4H), 4.22-4.34 (m, 1H), 4.40-4.60 (m, 2H), 5.14-5.31 (m, 1H), 6.46(br. s., 2H), 6.85-7.01 (m, 3H), 7.16-7.33 (m, 2H), 7.59-7.67 (m, 2H),7.69-7.80 (m, 2H), 8.38-8.54 (m, 1H). (partial resolution of thetwo-fold set of signals of the diastereomer mixture).

The diastereomer mixture was separated by preparative HPLC on chiralphase [Method 13a]: see Examples 189 and 190.

Example 1893-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-(2-methoxyphenyl)propylcarbamate (diastereomer I)

First-eluting diastereomer from the separation from Example 188.

Yield: 33 mg (9% of theory)

Chiral analytical HPLC [Method 9]: R_(t)=3.46 min

LC-MS [Method 5] R_(t)=1.01 min; MS [ESIpos]: m/z=572 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=1.81-2.00 (m, 2H), 3.79 (s, 3H), 3.81-4.07(m, 4H), 4.22-4.35 (m, 1H), 4.44-4.56 (m, 2H), 5.17-5.29 (m, 1H), 6.47(br. s., 2H), 6.87-7.01 (m, 3H), 7.19-7.33 (m, 2H), 7.63 (d, 2H), 7.76(d, 2H), 8.50 (d, 1H).

Example 1903-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-(2-methoxyphenyl)propylcarbamate (diastereomer II)

Last-eluting diastereomer from the separation from Example 188.

LC-MS [Method 5] R_(t)=1.00 min; MS [ESIpos]: m/z=572 (M+H)⁺

Chiral analytical HPLC [Method 9]: R_(t)=3.83 min

Yield: 47 mg (12% of theory)

¹H NMR (400 MHz, DMSO-d₆): δ=1.81-1.98 (m, 2H), 3.78 (s, 3H), 3.81-4.00(m, 4H), 4.21-4.34 (m, 1H), 4.42-4.58 (m, 2H), 5.17-5.26 (m, 1H), 6.44(br. s., 2H), 6.87-7.00 (m, 3H), 7.20-7.30 (m, 2H), 7.62 (d, 2H), 7.76(d, 2H), 8.48 (d, 1H).

Example 1912-({[3-(4-Chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-[2-(trifluoromethyl)phenyl]ethylcarbamate (enantiomer II)

A quantity of 30 mg (0.08 mmol) of[3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]aceticacid (preparation according to WO2007/134862, Example 154A) wasdissolved in 1 ml of DMF, and the solution was admixed with 21 mg (0.11mmol) of EDC and with 15 mg (0.11 mmol) of HOBt and subsequently stirredat room temperature for 20 minutes. Then 23 mg (0.09 mmol) of thecompound from Example 180A were added and the mixture was left withstirring at room temperature for 16 h. For work-up, 50 μl of 1Nhydrochloric acid were added and the crude product was purified directlyby preparative HPLC [Method 19]. This gave 34 mg (69% of theory) of thetarget compound.

LC-MS [Method 4] R_(t)=1.09 min; MS [ESIpos]: m/z=592 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.98 (dd, 1H), 4.13 (dd, 1H), 4.47-4.57 (m,2H), 5.01 (s, 2H), 5.37-5.44 (m, 1H), 6.59 (br. s., 2H), 7.02-7.17 (m,3H), 7.26-7.34 (m, 1H), 7.48-7.55 (m, 5H), 7.68-7.77 (m, 3H), 8.98 (d,1H).

The following compounds were obtained analogously:

¹H-NMR Reactant; (400 MHz) Example Yield LC/MS: No. Structure [% oftheory] R_(t) [Method] 192

WO2007/134862 Example 220A; 180A 60% (DMSO-d₆): δ = 0.62 (s, 9H), 3.67(s, 2H), 3.98 (dd, 1H), 4.11 (dd, 1H), 4.48 (s, 2H), 5.34-5.42 (m, 1H),6.60 (br. s., 2H), 7.48-7.54 (m, 1H), 7.57 (d, 2H), 7.62-7.75 (m, 5H),8.93 (d, 1H). R_(t) = 1.11 min; MS [ESIpos]: m/z = 554 (M + H)⁺ [4] 193

WO2007/134862 Example 221A; 180A 60% (DMSO-d₆): δ = 0.93 (s, 6H), 2.67(s, 3H), 3.77 (s, 2H), 3.97 (dd, 1H), 4.11 (dd, 1H), 4.47 (s, 2H),5.35-5.42 (m, 1H), 6.60 (br.s., 2H), 7.48-7.57 (m, 3H), 7.62 (d, 2H),7.66-7.75 (m, 3H), 8.93 (d, 1H). R_(t) = 1.03 min; MS [ESIpos]: m/z =570 (M + H)⁺ [4] 194

166A; 180A 61% (DMSO-d₆): δ = 3.99 (dd, 1H), 4.07-4.15 (m, 3H), 4.49 (s,2H), 4.82-4.90 (m, 1H), 4.98-5.03 (m, 1H), 5.36-5.44 (m, 1H), 5.59-5.70(m, 1H), 6.57 (br.s., 2H), 7.49-7.55 (m, 2H), 7.62 (dd, 1H), 7.68-7.76(m, 3H), 7.98 (d, 1H), 8.91 (d, 1H). R_(t) = 1.05 min; MS [ESIpos]: m/z= 602 and 604 (M + H)⁺ [4] 195

WO2007/134862 Example 21 219A; 180A 72% (DMSO-d₆): δ = 3.98 (dd, 1H),4.12 (dd, 1H), 4.52 (s, 2H), 4.69 (q, 2H), 5.35- 5.42 (m, 1H), 6.60(br.s., 2H), 7.48-7.55 (m, 1H), 7.58-7.63 (m, 2H), 7.65-7.76 (m, 5H),9.00 (d, 1H). R_(t) = 1.04 min; MS [ESIpos]: m/z = 566 (M + H)⁺ [4] 196

8A; 175A 39% (DMSO-d₆): δ = 3.49- 3.57 (m, 1H), 3.58-3.66 (m, 1H), 3.82(dd, 1H), 3.91-3.99 (m, 1H), 4.23- 4.28 (m, 1H), 4.47- 4.61 (m, 2H),5.09-5.14 (m, 1H), 5.22-5.30 (m, 1H), 6.88 (t, 1H), 7.32- 7.39 (m, 1H),7.41-7.45 (m, 1H), 7.52-7.57 (m, 1H), 7.60-7.64 (m, 2H), 7.71-7.76 (m,2H), 8.78- 8.83 (m, 1H). (partial resolution of the two-fold set ofsignals of the diastereomer mixture) R_(t) = 1.20 min; MS [ESIpos]: m/z= 553 and 555 (M + H)⁺ [3] 197

177A; 175A 51% (DMSO-d₆): δ = 2.55- 2.65 (m, 2H), 3.48-3.57 (m, 1H),3.58-3.66 (m, 1H), 3.97 (t, 2H), 4.48- 4.58 (m, 2H), 5.11 (t, 1H), 5.25(td, 1H), 7.35 (t, 1H), 7.42 (dd, 1H), 7.54 (dd, 1H), 7.59-7.68 (m, 4H),8.79 (d, 1H). R_(t) = 1.09 min; MS [ESIpos]: m/z = 537 and 539 (M + H)⁺[5] 198

77A; 175A 45% (DMSO-d₆): δ = 3.49- 3.57 (m, 1H), 3.58-3.67 (m, 1H), 4.58(s, 2H), 5.12 (t, 1H), 5.27 (td, 1H), 6.79-6.89 (m, 1H), 7.13-7.21 (m,1H), 7.33- 7.39 (m, 1H), 7.43 (dd, 1H), 7.55 (dd, 1H), 7.61- 7.69 (m,4H), 8.84 (d, 1H). R_(t) = 1.18 min; MS [ESIpos]: m/z = 533 and 537 (M +H)⁺ [5] 199

8A; 183A 45% (DMSO-d₆): δ = 3.82 (dd, 1H), 3.92-3.99 (m, 1H), 4.00-4.16(m, 2H), 4.21- 4.32 (m, 1H), 4.46- 4.58 (m, 2H), 5.40-5.49 (m, 1H), 6.89(t, 1H), 7.36-7.43 (m, 1H), 7.45- 7.50 (m, 1H), 7.56- 7.65 (m, 3H),7.71-7.76 (m, 2H), 8.95-9.01 (m, 1H). (partial resolution of thetwo-fold set of signals of the diastereomer mixture) R_(t) = 1.20 min;MS [ESIpos]: m/z = 596 and 598 (M + H)⁺ [3] 200

77A; 183A 47% (DMSO-d₆): δ = 4.00- 4.16 (m, 2H), 4.50-4.62 (m, 2H), 5.46(td, 1H), 6.60 (br.s., 2H), 6.85 (sxt, 1H), 7.14-7.21 (m, 1H), 7.37-7.42(m, 1H), 7.46- 7.50 (m, 1H), 7.57- 7.70 (m, 5H), 9.00 (d, 1H). R_(t) =1.23 min; MS [ESIpos]: m/z = 578 and 580 (M + H)⁺ [3] 201

177A; 183A 53% (DMSO-d₆): δ = 2.52- 2.68 (m, 2H), 3.97 (t, 2H),4.02-4.15 (m, 2H), 4.46-4.55 (m, 2H), 5.40- 5.47 (m, 1H), 6.40- 6.80 (mbr., 2H), 7.38 (t, 1H), 7.47 (dd, 1H), 7.56- 7.68 (m, 5H), 8.97 (d, 1H).R_(t) = 1.33 min; MS [ESIpos]: m/z = 580 and 582 (M + H)⁺ [3]

Example 2022-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-(2,3-dichlorophenyl)ethylcarbamate (diastereomer I)

First-eluting diastereomer from the separation of the diastereomermixture by Method 11b from Example 199.

Yield: 43 mg (32% of theory)

Chiral analytical HPLC [Method 12a]: R_(t)=4.50 min

LC-MS [Method 4] R_(t)=1.05 min; MS [ESIpos]: m/z=596 and 598 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.82 (dd, 1H), 3.95 (dd, 1H), 4.02-4.15 (m,2H), 4.22-4.33 (m, 1H), 4.46-4.58 (m, 2H), 5.41-5.48 (m, 1H), 6.60 (sbr., 2H), 6.91 (d, 1H), 7.39 (t, 1H), 7.45-7.50 (m, 1H), 7.56-7.66 (m,3H), 7.74 (d, 2H), 8.99 (d, 1H).

Example 2032-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-(2,3-dichlorophenyl)ethylcarbamate (diastereomer II)

Last-eluting diastereomer from the separation of the diastereomermixture by Method 11b from Example 199.

Yield: 50 mg (41% of theory)

Chiral analytical HPLC [Method 12a]: R_(t)=6.55 min

LC-MS [Method 4] R_(t)=1.05 min; MS [ESIpos]: m/z=596 and 598 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.82 (dd, 1H), 3.96 (dd, 1H), 4.02-4.16 (m,2H), 4.22-4.29 (m, 1H), 4.47-4.57 (m, 2H), 5.40-5.48 (m, 1H), 6.60 (sbr., 2H), 6.89 (d, 1H), 7.40 (t, 1H), 7.46-7.50 (m, 1H), 7.57-7.65 (m,3H), 7.74 (d, OH), 9.00 (d, 1H).

Example 2042-({[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethylcarbamate (enantiomer I)

First-eluting enantiomer from the separation of the enantiomer mixtureby Method 25 from Example 201.

Yield: 128 mg (36% of theory)

Chiral analytical HPLC [Method 27d]: R_(t)=4.35 min

LC-MS [Method 3] R_(t)=1.24 min; MS [ESIpos]: m/z=580 and 582 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.52-2.68 (m, 2H), 3.97 (t, 2H), 4.02-4.15(m, 2H), 4.46-4.55 (m, 2H), 5.40-5.47 (m, 1H), 6.40-6.80 (m br., 2H),7.38 (t, 1H), 7.47 (dd, 1H), 7.56-7.68 (m, 5H), 8.97 (d, 1H).

Example 2052-({[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethylcarbamate (enantiomer II)

Last-eluting enantiomer from the separation of the enantiomer mixture byMethod 25 from Example 201.

Yield: 135 mg (40% of theory)

Chiral analytical HPLC [Method 27d]: R_(t)=5.04 min

LC-MS [Method 3] R_(t)=1.24 min; MS [ESIpos]: m/z=580 and 582 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=2.52-2.68 (m, 2H), 3.97 (t, 2H), 4.02-4.15(m, 2H), 4.46-4.55 (m, 2H), 5.40-5.47 (m, 1H), 6.40-6.80 (m br., 2H),7.38 (t, 1H), 7.47 (dd, 1H), 7.56-7.68 (m, 5H), 8.97 (d, 1H).

Example 2062-({[4-(4-Chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]acetyl}amino)-2-[3-(trifluoromethyl)phenyl]ethylcarbamate (diastereomer mixture)

A quantity of 58 mg (0.11 mmol) of[4-(4-chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]aceticacid from Example 184A was dissolved in 2 ml of DMF, and the solutionwas admixed with 28 mg (0.15 mmol) of EDC and with 20 mg (0.15 mmol) ofHOBt and subsequently stirred at room temperature for 20 minutes. Then42 mg (0.12 mmol) of the compound from Example 183A were added and themixture was left with stirring at room temperature for 16 h. Forwork-up, 100 μl of 1N hydrochloric acid were added and the crude productwas purified directly by preparative HPLC [Method 19]. This gave 13 mg(18% of theory) of the target compound.

LC-MS [Method 3] R_(t)=1.23 min; MS [ESIpos]: m/z=595 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.74 (dd, 1H), 3.87 (dd, 1H), 4.05-4.15 (m,2H), 4.19-4.28 (m, 1H), 4.32-4.39 (m, 2H), 5.12-5.21 (m, 1H), 6.59 (sbr., 2H), 6.68-6.74 (m, 2H), 7.47-7.77 (m, 8H), 8.87 (d, 1H).

Example 2072-({[4-(4-Chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]acetyl}amino)-2-[2-(trifluoromethyl)phenyl]ethylcarbamate (diastereomer mixture)

In the same way as for the compound from Example 206, 58 mg (0.11 mmol)of[4-(4-chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]aceticacid from Example 185A were reacted with 42 mg (0.12 mmol) of thecompound from Example 180A. This gave 12 mg (18% of theory) of thetarget compound.

LC-MS [Method 5] R_(t)=1.06 min; MS [ESIpos]: m/z=595 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.73 (dd, 1H), 3.86 (dd, 1H), 3.98 (dd,1H), 4.13 (dd, 1H), 4.19-4.27 (m, 1H), 4.27-4.38 (m, 2H), 5.37-5.45 (m,1H), 6.59 (s br., 2H), 6.68-6.74 (m, 2H), 7.47-7.56 (m, 6H), 7.69-7.77(m, 4H), 8.95 (d, 1H).

B. EVALUATION OF THE PHARMACOLOGICAL ACTIVITY Abbreviations

-   EDTA Ethylenediaminetetraacetic acid-   DMEM Dulbecco's Modified Eagle Medium-   FCS Foetal calf serum-   HEPES 4-(2-Hydroxyethyl)-1-piperazineethanesulphonic acid-   SmGM Smooth Muscle Cell Growth Media-   Tris-HCl 2-Amino-2-(hydroxymethyl)-1,3-propanediol hydrochloride-   UtSMC Uterine Smooth Muscle Cells

The pharmacological action of the compounds of the invention can beshown in the following assays:

B-1. Cellular In Vitro Assay for Determining the Vasopressin ReceptorActivity

The identification of agonists and antagonists of the V1a and V2vasopressin receptors from humans and rats and also the quantificationof the activity of the substances described here took place usingrecombinant cell lines. These cells derive originally from a hamsterovary epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC: AmericanType Culture Collection, Manassas, Va. 20108, USA). The test cell linesconstitutively express a modified form of the calcium-sensitivephotoprotein aequorin, which, after reconstitution with the cofactorcoelenterazine, emits light when there are increases in the free calciumconcentration (Rizzuto R., Simpson A. W., Brini M., Pozzan T.; Nature358 (1992) 325-327). In addition, the cells are stably transfected withthe human or rat V1a or V2 receptors. In the case of the Gs-coupling V2receptors, the cells are stably transfected with a further gene, whichcodes for the promiscuous G_(α16) protein (Amatruda T. T., Steele D. A.,Slepak V. Z., Simon M. I., Proc. Nat. Acad. Sci. USA 88 (1991),5587-5591), either independently or as a fusion gene. The resultingvasopressin receptor test cells react to stimulation of therecombinantly expressed vasopressin receptors by intracellular releaseof calcium ions, which can be quantified by the resulting aequorinluminescence using a suitable luminometer (Milligan G., Marshall F.,Rees S., Trends in Pharmaco. Sci. 17 (1996) 235-237).

Test Procedure

On the day before the assay, the cells are plated out in culture medium(DMEM, 10% FCS, 2 mM glutamine, 10 mM HEPES) in 384-well microtiterplates and kept in a cell incubator (96% humidity, 5% v/v carbondioxide, 37° C.). On the day of the assay, the culture medium isreplaced by a Tyrode solution (140 mM sodium chloride, 5 mM potassiumchloride, 1 mM magnesium chloride, 2 mM calcium chloride, 20 mM glucose,20 mM HEPES), which additionally contains the cofactor coelenterazine(50 μM), and the microtiter plate is then incubated for a further 3-4hours. The test substances in various concentrations are placed for 10to 20 minutes in the wells of the microtiter plate before the agonist[Arg8]-vasopressin is added, and the resulting light signal is measuredimmediately in the luminometer. The IC50 values are calculated using theGraphPad PRISM computer program (Version 3.02).

The table below lists representative IC₅₀ values for the compounds ofthe invention on the cell line transfected with the human V1a or V2receptor:

TABLE 1 Example No. IC₅₀ hV1a [μM] IC₅₀ hV2 [μM] 2 0.0076 0.0026 100.0104 0.0063 14 0.001 0.0089 20 0.0015 0.0063 24 0.0045 0.0013 260.0009 0.0032 34 0.003 0.0015 39 0.0014 0.0078 44 0.044 0.0017 45 0.00550.0025 48 0.0052 0.0044 51 0.001 0.0085 53 0.0015 0.0049 57 0.00290.0022 60 0.0005 0.0045 62 0.0036 0.001 65 0.0168 0.0168 69 0.00160.0097 70 0.0016 0.0099 73 0.0108 0.0016 74 0.0216 0.0024 75 0.5130.0592 78 0.0211 0.0304 87 0.0038 0.0058 89 2.88 0.29 90 0.0886 0.231 940.251 0.0723 95 0.0573 0.0192 96 0.0713 0.0402 112 0.0024 0.006 1150.0035 0.0076 121 0.0009 0.0014 126 0.0018 0.0018 136 0.0039 0.024 1410.036 0.0048 144 0.0014 0.0139 149 0.002 0.015 152 0.0022 0.0071 1560.0019 0.01 157 0.0124 0.0051 159 0.0043 0.0018 163 0.594 0.0077 1670.003 0.0054 168 0.087 0.076 172 0.091 0.136 182 0.304 0.028 184 0.0720.0266 185 0.055 0.045 188 0.0082 0.0099 191 0.0023 0.0248 203 0.00270.0044 207 0.0033 0.101

B-2. Cellular In Vitro Assay for Detecting the Action of Vasopressin V1aReceptor Antagonists on the Regulation of Pro-Fibrotic Genes

The cell line H9C2 described as of cardiomyocyte type (American TypeCulture Collection ATCC No. CRL-1446), isolated from rat cardiac tissue,endogenously expresses the vasopressin VIA receptor AVPR1A in high copynumber, whereas the AVPR2 expression cannot be detected. For cell assayson the inhibition of the AVPR1A receptor-dependent regulation of geneexpression by receptor antagonists, the procedure is as follows:

H9C2 cells are seeded in 12-well microtiter plates for cell culture, ata cell density of 100 000 cells/well, in 1.0 ml of Opti-MEM medium(Invitrogen Corp. Carlsbad Calif., USA, Cat. No. 11058-021) with 2% FCSand 1% penicillin/streptomycin solution (Invitrogen Cat. No. 10378-016),and held in a cell incubator (96% humidity, 5% v/v carbon dioxide, 37°C.). After 24 hours, sets of three wells (triplicate) are charged withvehicle solution (negative control), vasopressin solution:[Arg8]-vasopressin acetate (Sigma Cat. No. V9879) or test substances(dissolved in vehicle: water with 20% by volume ethanol) and vasopressinsolution. In the cell culture, the final vasopressin concentration is0.05 μM. The test substance solution is added to the cell culture insmall volumes, and so a final concentration of 0.1% of ethanol in thecell assay is not exceeded. After an incubation time of 6 hours, theculture supernatant is drawn off under suction, the adherent cells arelysed in 250 μl of RLT buffer (Qiagen, Ratingen, Cat. No. 79216), andthe RNA is isolated from this lysate using the RNeasy kit (Qiagen, Cat.No. 74104). This is followed by DNAse digestion (Invitrogen Cat. No.18068-015), cDNA synthesis (Promaga ImProm-R Reverse TranscriptionSystem Cat. No. A3800) and RTPCR using the pPCR MasterMix RT-QP2X-03-075from Eurogentec, Seraing, Belgium. All procedures take place inaccordance with the working protocols of the test reagents'manufacturers. The primer sets for the RTPCR are selected on the basisof the mRNA gene sequences (NCBI Genbank Entrez Nucleotide Data Base)using the Primer-3Plus program with 6-FAM—TAMRA labelled probes. TheRTPCR for determining the relative mRNA expression in the cells of thevarious assay batches is carried out using the Applied Biosystems ABIPrism 7700 Sequence Detector in 96-well or 384-well microtiter plateformat in accordance with the instrument operating instructions. Therelative gene expression is represented by the delta-delta Ct value[Applied Biosystems, User Bulletin No. 2 ABI Prism 7700 SDS Dec. 11,1997 (updated 10/2001)] with reference to the level of expression of theribosomal protein L-32 gene (Genbank Acc. No. NM_(—)013226) and thethreshold Ct value of Ct=35.

B-3. In Vivo Test for Detection of Cardiovascular Effect: Blood PressureMeasurement on Anaesthetised Rats (Vasopressin ‘Challenge’ Model)

In male Sprague-Dawley rats (250-350 g body weight) underketamine/xylazine/pentobarbital injection anaesthesia, polyethylenetubes (PE-50; Intramedic®), which are prefilled with heparin-containing(500 IU/ml) isotonic sodium chloride solution, are introduced into thejugular vein and the femoral vein and then tied in. Via one venousaccess, with the aid of a syringe, arginine-vasopressin is injected; thetest substances are administered via the second venous access. Fordetermination of the cystolic blood pressure, a pressure catheter(Millar SPR-320 2F) is tied into the carotid artery. The arterialcatheter is connected to a pressure transducer which feeds its signalsto a recording computer equipped with suitable recording software. In atypical experiment the experimental animal is administered 3-4successive bolus injections at intervals of 10-15 min with a definedamount of arginine-vasopressin (30 ng/kg) in isotonic sodium chloridesolution and, when the blood pressure has reached initial levels again,the substance under test is administered as a bolus, with subsequentongoing infusion, in a suitable solvent. After this, at definedintervals (10-15 min), the same amount of vasopressin as at the start isadministered again. On the basis of the blood pressure values, adetermination is made of the extent to which the test substancecounteracts the hypertensive effect of the vasopressin. Control animalsreceive only solvent instead of the test substance.

Following intravenous administration, the compounds of the invention, incomparison to the solvent controls, bring about an inhibition in theblood pressure increase caused by arginine-vasopressin.

B-4. In Vivo Assay for Detecting the Cardiovascular Effect: DiuresisInvestigations on Conscious Rats in Metabolism Cages

Wistar rats (220-400 g body weight) are kept with free access to feed(Altromin) and drinking water. During the experiment, the animals arekept with free access to drinking water for 4 to 8 hours individually inmetabolism cages suitable for rats of this weight class (TecniplastDeutschland GmbH, D-82383Hohenpeiβenberg). At the beginning of theexperiment, the animals are administered the substance under test in avolume of 1 to 3 ml/kg body weight of a suitable solvent by means ofgavage into the stomach. Control animals receive only solvent. Controlsand substance tests are carried out in parallel on the same day. Controlgroups and substance-dose groups each consist of 4 to 8 animals. Duringthe experiment, the urine excreted by the animals is collectedcontinuously in a receiver at the base of the cage. The volume of urineper unit time is determined separately for each animal, and theconcentration of the sodium and potassium ions excreted in the urine ismeasured by standard methods of flame photometry. To obtain a sufficientvolume of urine, the animals are given a defined amount of water bygavage at the beginning of the experiment (typically 10 ml per kilogramof body weight). Before the beginning of the experiment and after theend of the experiment, the body weight of the individual animals istaken.

Following oral administration, in comparison with control animals, thecompounds of the invention bring about an increased excretion of urine,which is based essentially on an increased excretion of water(aquaresis).

B-5. In Vivo Assay for Detecting the Cardiovascular Effect: HaemodynamicInvestigations on Anaesthetised Dogs

Male or female mongrel dogs (Mongrels, Marshall BioResources, USA) witha weight of between 20 and 30 kg are anaesthetised with pentobarbital(30 mg/kg iv, Narcoren®, Merial, Germany) for the surgical interventionsand the haemodynamic and functional investigation terminii. Alcuroniumchloride (Alloferin®, ICN Pharmaceuticals, Germany, 3 mg/animal iv)serves additionally as a muscle relaxant. The dogs are intubated andventilated with an oxygen/ambient air mixture (40/60%) (about 5-6 L/min)Ventilation takes place using a ventilator from Draeger (Sulla 808) andis monitored using a carbon dioxide analyser (Engström).

The anaesthesia is maintained by continual infusion of pentobarbital (50μg/kg/min); fentanyl is used as an analgesic (10 μg/kg/h). Onealternative to pentobarbital is to use isoflurane (1-2% by volume).

In preparatory interventions, the dogs are fitted with a cardiacpacemaker.

-   -   At a time of 21 days before the first drug testing (i.e. start        of experiment), a cardiac pacemaker from Biotronik (Logos®) is        implanted into a subcutaneous skin pocket and is contacted with        the heart via a pacemaker electrode which is advanced through        the external jugular vein, with illumination, into the right        ventricle.    -   At the same time as the implanting of the pacemaker, through        retrograde advancing of a 7F biopsy forceps (Cordis) via a        sheath introducer (Avanti+®; Cordis) in the fermoral artery, and        after atraumatic passage through the aortic valve, there is        defined lesion of the mitral valve, with monitoring by echo        cardiography and illumination. Thereafter all of the accesses        are removed and the dog wakes spontaneously from the        anaesthesia.    -   After a further 7 days (i.e. 14 days before the first drug        testing), the above pacemaker is activated and the heart is        stimulated at a frequency of 220 beats per minute.

The actual drug testing experiments take place 14 and 28 days after thebeginning of pacemaker stimulation, using the following instrumentation:

-   -   Bladder catheter for bladder relief and for measuring the flow        of urine    -   ECG leads to the extremities (for ECG measurement)    -   Introduction of an NaCl-filled Fluidmedic PE-300 tube into the        femoral artery. This tube is connected to a pressure sensor        (Braun Melsungen, Melsungen, Germany) for measuring the systemic        blood pressure    -   Introduction of a Millar Tip catheter (type 350 PC, Millar        Instruments, Houston, USA) through the left atrium or through a        port secured in the carotid artery, for measuring cardiac        haemodynamics    -   Introduction of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards,        Irvine, USA) via the jugular vein into the pulmonary artery, for        measuring the cardiac output, oxygen saturation, pulmonary        arterial pressures and central venous pressure    -   Siting of a Braunüle in the cephalic vein, for infusing        pentobarbital, for liquid replacement and for blood sampling        (determination of the plasma levels of substance or other        clinical blood values)    -   Siting of a Braunüle in the saphenous vein, for infusing        fentanyl and for administration of substance    -   Infusion of vasopressin (Sigma) in increasing dosage, up to a        dose of 4 mU/kg/min. The pharmacological substances are then        tested with this dosage.

The primary signals are amplified if necessary (Gould amplifier, GouldInstrument Systems, Valley View, USA) or Edwards Vigilance-Monitor(Edwards, Irvine, USA) and subsequently fed into the Ponemah system(DataSciences Inc, Minneapolis, USA) for evaluation. The signals arerecorded continuously throughout the experimental period, and arefurther processed digitally by the said software, and averaged over 30s.

C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS

The compounds of the invention can be converted into pharmaceuticalpreparations in the following ways:

Tablet: Composition:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate),50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm

Production:

The mixture of compound of the invention, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Afterdrying, the granules are mixed with the magnesium stearate for 5minutes. This mixture is compressed using a conventional tableting press(for tablet format see above). The guideline compressive force used forcompression is 15 kN.

Suspension for Oral Administration: Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g ofwater.

A single dose of 100 mg of the compound of the invention is given by 10ml of oral suspension.

Production:

The Rhodigel is suspended in ethanol, and the compound of the inventionis added to the suspension. The water is added with stirring. Stirringis continued for about 6 h until the swelling of the Rhodigel is ended.

Solution for Oral Administration: Composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 gof polyethylene glycol 400. A single dose of 100 mg of the compound ofthe invention is given by 20 g of oral solution.

Production:

The compound of the invention is suspended with stirring in the mixtureof polyethylene glycol and polysorbate. The stirring operation continuesuntil the compound of the invention is fully dissolved.

I.V. Solution:

The compound of the invention is dissolved at a concentration belowsaturation solubility in a physiologically tolerated solvent (e.g.isotonic saline solution, 5% glucose solution and/or 30% PEG 400solution). The solution is sterile-filtered and dispensed into sterile,pyrogen-free injection containers.

1. A compound of the formula (I)

in which A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B)) —*,where * is the attachment site to R³, R^(6A) is hydrogen, (C₁-C₄) alkylor trifluoromethyl, R^(6B) is hydrogen or (C₁-C₄) alkyl, R^(7A) ishydrogen, (C₁-C₄) alkyl or trifluoromethyl, R^(7B) is hydrogen or(C₁-C₄) alkyl, Q is CH or N, R¹ is (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl or (C₃-C₇) cycloalkyl, where (C₁-C₆) alkyl, (C₂-C₆)alkenyl and (C₂-C₆) alkynyl may be substituted by 1 to 3 substituentsindependently of one another selected from the group consisting ofdeuterium, halogen, cyano, oxo, hydroxyl, trifluoromethyl, (C₃-C₇)cycloalkyl, (C₁-C₆) alkoxy, trifluoromethoxy and phenyl, in which(C₃-C₇) cycloalkyl may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting of(C₁-C₄) alkyl, oxo, hydroxyl, (C₁-C₄) alkoxy and amino, and in which(C₁-C₆) alkoxy may be substituted by 1 or 2 substituents independentlyof one another selected from the group consisting of amino, hydroxyl,(C₁-C₄) alkoxy, hydroxycarbonyl and (C₁-C₄) alkoxycarbonyl, and in whichphenyl may be substituted by 1 to 3 substituents independently of oneanother selected from the group consisting of halogen, cyano, nitro,(C₁-C₄) alkyl, trifluoromethyl, hydroxyl, hydroxymethyl, (C₁-C₄) alkoxy,trifluoromethoxy, (C₁-C₄) alkoxymethyl, hydroxycarbonyl, (C₁-C₄)alkoxycarbonyl, aminocarbonyl, mono-(C₁-C₄) alkylaminocarbonyl anddi-(C₁-C₄) alkylaminocarbonyl, and where (C₃-C₇) cycloalkyl may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of fluorine, (C₁-C₄) alkyl, (C₁-C₄) alkoxy,hydroxy, amino and oxo, R² is benzothienyl, phenyl, thienyl or furyl,where benzothienyl, phenyl, thienyl and furyl may be substituted by 1 to3 substituents independently of one another selected from the groupconsisting of halogen, cyano, nitro, (C₁-C₄) alkyl, trifluoromethyl,hydroxyl, (C₁-C₄) alkoxy and trifluoromethoxy, R³ is trifluoromethyl,hydroxyl, trifluoromethoxy, (C₁-C₄) alkoxy, (C₃-C₇) cycloalkoxy, nitro,amino, —NR⁸—C(═O)—R⁹, —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³, —O—C(═O)—NR¹⁴R¹⁵,—NR¹⁶—C(═O)—NR¹⁷R¹⁸, —NR¹⁹—C(═O)—OR²⁰, —S(═O)_(n)R²¹, —O—SO₂—NR²⁴R²⁵,—NR²⁶—SO₂—NR²⁷R²⁸ or —NR³⁰R³¹, where R⁸ is hydrogen or (C₁-C₄) alkyl, R⁹is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl, or R⁸ and R⁹ togetherwith the atoms to which they are attached form a 5- to 7-memberedheterocycle, where the 5- to 7-membered heterocycle may be substitutedby 1 or 2 substituents independently of one another selected from thegroup consisting of fluorine, (C₁-C₄) alkyl and trifluoromethyl, R¹⁰ ishydrogen or (C₁-C₄) alkyl, R¹¹ is (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,or R¹⁰ and R¹¹ together with the atoms to which they are attached form a5- to 7-membered heterocycle, where the 5- to 7-membered heterocycle maybe substituted by 1 or 2 substituents independently of one anotherselected from the group consisting of fluorine, (C₁-C₄) alkyl andtrifluoromethyl, R¹² is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,R¹³ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl, or R¹² and R¹³together with the nitrogen atom to which they are attached form a 4- to7-membered heterocycle, where the 4- to 7-membered heterocycle may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of fluorine, oxo, hydroxyl, (C₁-C₄) alkyl andtrifluoromethyl, R¹⁴ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,R¹⁵ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl, or R¹⁴ and R¹⁵together with the nitrogen atom to which they are attached form a 4- to7-membered heterocycle, where the 4- to 7-membered heterocycle may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of fluorine, oxo, hydroxyl, (C₁-C₄) alkyl andtrifluoromethyl, R¹⁶ is hydrogen or (C₁-C₄) alkyl, R¹⁷ is hydrogen,(C₁-C₄) alkyl or (C₃-C₇) cycloalkyl, R¹⁸ is hydrogen, (C₁-C₄) alkyl or(C₃-C₇) cycloalkyl, or R¹⁶ and R¹⁷ together with the nitrogen atoms towhich they are attached form a 5- to 7-membered heterocycle, where the5- to 7-membered heterocycle may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting offluorine, trifluoromethyl and (C₁-C₄) alkyl, or R¹⁷ and R¹⁸ togetherwith the nitrogen atom to which they are attached form a 4- to7-membered heterocycle, where the 4- to 7-membered heterocycle may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of fluorine, oxo, hydroxyl, (C₁-C₄) alkyl andtrifluoromethyl, R¹⁹ is hydrogen or (C₁-C₄) alkyl, R²⁰ is (C₁-C₄) alkylor (C₃-C₇) cycloalkyl, or R¹⁹ and R²⁰ together with the atoms to whichthey are attached form a 5- to 7-membered heterocycle, where the 5- to7-membered heterocycle may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting offluorine, (C₁-C₄) alkyl and trifluoromethyl, n is a number 0, 1 or 2,R²¹ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl, R²⁴ is hydrogen,(C₁-C₄) alkyl or (C₃-C₇) cycloalkyl, R²⁵ is hydrogen, (C₁-C₄) alkyl or(C₃-C₇) cycloalkyl, or R²⁴ and R²⁵ together with the nitrogen atom towhich they are attached form a 4- to 7-membered heterocycle, where the4- to 7-membered heterocycle may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting offluorine, oxo, hydroxyl, (C₁-C₄) alkyl and trifluoromethyl, R²⁶ ishydrogen or (C₁-C₄) alkyl, R²⁷ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇)cycloalkyl, R²⁸ is hydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl, or R²⁶and R²⁷ together with the nitrogen atoms to which they are attached forma 5- to 7-membered heterocycle, where the 5- to 7-membered heterocyclemay be substituted by 1 or 2 substituents independently of one anotherselected from the group consisting of fluorine, trifluoromethyl and(C₁-C₄) alkyl, or R²⁷ and R²⁸ together with the nitrogen atom to whichthey are attached form a 4- to 7-membered heterocycle, where the 4- to7-membered heterocycle may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting offluorine, oxo, hydroxyl and (C₁-C₄) alkyl, R³⁰ is hydrogen, (C₁-C₄)alkyl or (C₃-C₇) cycloalkyl, R³¹ is (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl,or R³⁰ and R³¹ together with the nitrogen atom to which they areattached form a 4- to 7-membered heterocycle, where the 4- to 7-memberedheterocycle may be substituted by 1 or 2 substituents independently ofone another selected from the group consisting of fluorine, oxo,hydroxyl, (C₁-C₄) alkyl and trifluoromethyl, R⁴ is phenyl, naphthyl or5- to 10-membered heteroaryl, where phenyl, naphthyl and 5- to10-membered heteroaryl may be substituted by 1 to 3 substituentsindependently of one another selected from the group consisting ofhalogen, cyano, nitro, (C₁-C₄) alkyl, difluoromethyl, trifluoro-methyl,hydroxyl, (C₁-C₄) alkoxy, difluoromethoxy and trifluoromethoxy, R⁵ ishydrogen, deuterium, trifluoromethyl or (C₁-C₄) alkyl, R²⁹ is hydrogenor (C₁-C₄) alkyl, or a salt thereof.
 2. The compound of claim 1, inwhich A is —C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))—*,where * is the attachment site to R³, R^(6A) is hydrogen, methyl ortrifluoromethyl, R^(6B) is hydrogen or methyl, R^(7A) is hydrogen,methyl or trifluoromethyl, R^(7B) is hydrogen or methyl, Q is CH or N,R¹ is (C₁-C₆) alkyl, (C₂-C₆) alkenyl or (C₃-C₆) cycloalkyl, where(C₁-C₆) alkyl and (C₂-C₆) alkenyl may be substituted by 1 to 3substituents independently of one another selected from the groupconsisting of fluorine, chlorine, cyano, oxo, hydroxyl, trifluoromethyl,(C₃-C₆) cycloalkyl, (C₁-C₄) alkoxy, trifluoromethoxy and phenyl, inwhich (C₃-C₆) cycloalkyl may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting ofmethyl, ethyl, oxo, hydroxyl, methoxy, ethoxy and amino, and in whichphenyl may be substituted by a substituent selected from the groupconsisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl,methoxy, ethoxy, trifluoromethoxy, methoxymethyl, ethoxymethyl,hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and aminocarbonyl, andwhere (C₃-C₆) cycloalkyl may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting offluorine, methyl, ethyl, methoxy, ethoxy, hydroxyl, amino and oxo, R² isbenzothien-2-yl, phenyl or thienyl, where benzothien-2-yl, phenyl andthienyl may be substituted by 1 or 2 substituents independently of oneanother selected from the group consisting of fluorine, chlorine,bromine, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy andtrifluoromethoxy, R³ is trifluoromethyl, hydroxyl, amino, —NR⁸—C(═O)—R⁹,—NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³, —O—C(═O)—NR¹⁴R¹⁵, —NR¹⁶—C(═O)—NR¹⁷R¹⁸,—NR¹⁹—C(═O)—OR²⁰, —S(═O)_(n)R²¹, —O—SO₂—NR²⁴R²⁵ or —NR²⁶—SO₂—NR²⁷R²⁸—,where R⁸ is hydrogen or methyl, R⁹ is (C₁-C₄) alkyl, or R⁸ and R⁹together with the atoms to which they are attached form a 5- to7-membered heterocycle, R¹⁰ is hydrogen or methyl, R¹¹ is (C₁-C₄) alkyl,or R¹⁰ and R¹¹ together with the atoms to which they are attached form a5- to 7-membered heterocycle, R¹² is (C₁-C₄) alkyl, R¹³ is (C₁-C₄)alkyl, R¹⁴ is hydrogen or (C₁-C₄) alkyl, R¹⁵ is hydrogen, (C₁-C₄) alkylor (C₃-C₇) cycloalkyl, or R¹⁴ and R¹⁵ together with the nitrogen atom towhich they are attached form a 4- to 7-membered heterocycle, R¹⁶ ishydrogen or (C₁-C₄) alkyl, R¹⁷ is hydrogen or (C₁-C₄) alkyl, R¹⁸ ishydrogen, (C₁-C₄) alkyl or (C₃-C₇) cycloalkyl, or R¹⁶ and R¹⁷ togetherwith the nitrogen atoms to which they are attached form a 5- to7-membered heterocycle, R¹⁹ is hydrogen or methyl, R²⁰ is (C₁-C₄) alkyl,or R¹⁹ and R²⁰ together with the atoms to which they are attached form a5- to 7-membered heterocycle, n is a number 0, 1 or 2, R²¹ is (C₁-C₄)alkyl, R²⁴ is hydrogen or methyl, R²⁵ is hydrogen or methyl, R²⁶ ishydrogen or methyl, R²⁷ is hydrogen or (C₁-C₄) alkyl, R²⁸ is hydrogen or(C₁-C₄) alkyl, or R²⁶ and R²⁷ together with the nitrogen atoms to whichthey are attached form a 5- to 7-membered heterocycle, R⁴ is phenyl,where phenyl may be substituted by 1 to 3 substituents independently ofone another selected from the group consisting of fluorine, chlorine,cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxyl,methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, R⁵ is hydrogen,deuterium, trifluoromethyl, methyl or ethyl, R²⁹ is hydrogen or methyl,or a salt thereof.
 3. The compound of the claim 1, in which A is—C(R^(6A)R^(6B))—* or —C(R^(6A)R^(6B))—C(R^(7A)R^(7B))_(—*,) where isthe attachment site to R³, R^(6A) is hydrogen or trifluoromethyl, R^(6B)is hydrogen, R^(7A) is hydrogen, R^(7B) is hydrogen, Q is N, R¹ is(C₂-C₄) alkyl, (C₂-C₄) alkenyl or cyclopropyl, where (C₂-C₄) alkyl and(C₂-C₄) alkenyl may be substituted by 1 or 2 substituents independentlyof one another selected from the group consisting of fluorine, oxo,hydroxyl and trifluoromethyl, R² is phenyl, where phenyl may besubstituted by a substituent selected from the group consisting offluorine or chlorine, R³ is trifluoromethyl, hydroxyl, amino,—NR⁸—C(═O)—R⁹, —NR¹⁰—SO₂—R¹¹, —SO₂—NR¹²R¹³, —O—C(═O)—NR¹⁴R¹⁵,—NR¹⁶—C(═O)—NR¹⁷R¹⁸, —NR¹⁹—C(═O)—OR²⁰, —S(═O)_(n)R²¹ or—NR²⁶—SO₂—NR²⁷R²⁸—, where R⁸ is hydrogen, R⁹ is methyl, R¹⁰ is hydrogen,R¹¹ is methyl or ethyl, R¹² is methyl, R¹³ is methyl, R¹⁴ is hydrogen ormethyl, R¹⁵ is hydrogen, methyl or ethyl, R¹⁶ is hydrogen, R¹⁷ ishydrogen or methyl, R¹⁸ is hydrogen, methyl or ethyl, or R¹⁶ and R¹⁷together with the nitrogen atoms to which they are attached form a2-oxoimidazolidin-1-yl or a 2-oxotetrahydropyrimidin-1(2H)-yl ring, R¹⁹is hydrogen, R²⁰ is methyl or ethyl, or R¹⁹ and R²⁰ together with theatoms to which they are attached form a 2-oxo-1,3-oxazolidin-3-yl or2-oxo-1,3-oxazinan-3-yl ring, n is a number 0 or 2, R²¹ is methyl, R²⁶is hydrogen, R²⁷ is hydrogen, R²⁸ is hydrogen, R⁴ is a group of theformula

where # is the attachment site to —C(R⁵)(AR³)N—, R²² is hydrogen,fluorine, chlorine, trifluoromethyl and methoxy, R²³ is hydrogen,fluorine, chlorine, trifluoromethyl and methoxy, where at least one ofthe radicals R²² and R²³ is other than hydrogen, R⁵ is hydrogen ormethyl, R²⁹ is hydrogen, or a salt thereof.
 4. A process for preparing acompound of claim 1, comprising [A] coupling a compound of the formula(II)

in which Q, R¹ and R² are each as defined in claims 1 to 3 in an inertsolvent, with activation of the carboxylic acid function, to a compoundof the formula (III)

in which A, R³, R⁴, R⁵ and R²⁹ are each as defined in claim 1, or [B]reacting a compound of the formula (IV)

in which Q, R¹ and R² are each as defined in claims 1 to 3 in an inertsolvent, in the presence of a base, with a compound of the formula (V)

in which A, R³, R⁴, R⁵ and R²⁹ are each as defined in claim 1 and X¹ isa leaving group, such as halogen, mesylate or tosylate, for example, andoptionally converting the resulting compounds of formula (I) with a (i)solvents and/or (ii) bases or acid into a salt thereof.
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. A pharmaceutical composition comprising acompound of claim 1 and an inert, non-toxic, pharmaceutically suitableexcipient.
 9. The pharmaceutical composition of claim 8, furthercomprising at least one active ingredient selected from the groupconsisting of a diuretic, an angiotensin AII antagonist, an ACEinhibitor, a beta receptor blocker, a mineralocorticoid receptorantagonist, an organic nitrate, an NO donor, and a substances withpositive inotropic activity.
 10. (canceled)
 11. A method for thetreatment and/or prophylaxis of acute and chronic cardiac insufficiency,hypervolaemic and euvolaemic hyponatraemia, liver cirrhosis, ascites,oedemas and the syndrome of inadequate ADH secretion (SIADH) comprisingadministering to a human or animal in need thereof, an effective amountof at least one compound of claim
 1. 12. A method for the treatmentand/or prophylaxis of acute and chronic cardiac insufficiency,hypervolaemic and euvolaemic hyponatraemia, liver cirrhosis, ascites,oedemas and the syndrome of inadequate ADH secretion (SIADH), comprisingadministering to a human or animal in need thereof, an effective amountof at least one pharmaceutical composition of claim 8.